Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2)

CREST-2 Administrative Supplement – Clinical Research Monitor PROJECT SUMMARY The Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2, U01 NS080168) consists of two parallel randomized trials in patients with asymptomatic high- grade carotid artery stenosis. One trial compares Intensive Medical Management (IMM) plus carotid endarterectomy to IMM alone, and the other compares IMM plus carotid artery stenting to IMM alone. The trial is registered with clinicaltrials.gov (NCT02089217). Carotid stent use is FDA-approved for revascularization of carotid stenosis for patients who meet criteria for being high-risk for complications from endarterectomy (so-called SAPPHIRE trial-type patients). CREST-2 approved stent operators can use FDA-approved devices off-label for the indication of revascularization of non-high-risk patients in the context of the trial through an FDA Investigational Device Exemption (IDE G130221). CREST-2 is a complex trial from the perspective of protecting human subjects, as there are widely divergent views of what constitutes equipoise for patients with asymptomatic carotid stenosis, ranging from the view that nearly everyone requires revascularization to just the opposite. Properly securing written informed consent is vital for protection of subjects and minimizing crossover events from medicine to revascularization is vital for ensuring the validity of the science. Monitoring plays a crucial role in ensuring the protection of subjects and the validity of the science. Monitoring is required for the FDA and NINDS as well. As of September 18, 2022, CREST-2 has enrolled a total of 2,137 patients: 1143 in the endarterectomy trial and 994 in the stenting trial. Patients have been enrolled across 182 sites (170 US and twelve international). Site monitoring has always been a part of the CREST-2 trial. The Covid-19 pandemic forced a dramatic shift in our monitoring from on-site to remote by live video conferencing. To be cost-effective, the Clinical Coordinating Center has taken on the responsibility of hiring and managing the monitor rather than outsourcing the responsibility to a Clinical Research Organization. While this was successful for many years, challenges in the labor force caused us to lose our two monitors. Currently we are temporizing with three site managers performing quality control checks on sites. We believe this dilution of their responsibilities has had a negative impact on study-wide recruitment. We prioritize quality control checks on sites that were recently activated, sites with a high number of randomizations, and sites with recent randomizations. The proposal included in this administrative supplement provides a plan and corresponding justification for hiring one full-time clinical research monitor to provide on-site and remote monitoring for CREST-2 to pursue the following specific aim: Resume site-level source document verification in the CREST-2 trial for fiscal year 2022- 2023 to assure protection of human subjects and the scientific integrity and validity of the trial.