Abstract The Early Detection Initiative (EDI) is an innovative study designed to build a platform that will evaluate novel approaches to early detection of resectable pancreatic ductal adenocarcinoma (PDAC) in patients over age 50 with new onset hyperglycemia and diabetes (NOD). This randomized controlled trial (RCT) of algorithm-based screening for PDAC uses a modified Zelen’s design with post-randomization consent. Eligible subjects are identified through electronic medical record (EMR) surveillance and randomized 1:1 to the Observation or Intervention Arm. The Enriching New-onset Diabetes for Pancreatic Cancer (ENDPAC) score, an algorithm that further risk stratifies NOD based on age and changes in weight and glycemic parameters, is calculated in the Intervention Arm. Consenting subjects with ENDPAC >0 have Computerized Tomography (CT) scan imaging for PDAC detection; potential harm, including over-diagnosis, is also estimated. At the time of abstract submission >2000 individuals have been randomized and >50 subjects consented for CT imaging. EDI version 2 adds several innovations in response to challenges encountered and experience gained so far. Most significantly, EDI v2 has a platform design with a common control arm and allows for multiple intervention arms. This opens the door for evaluating future new biomarkers for PDAC early detection in a high–risk NOD population, including new blood-based biomarkers for the early detection of cancer that are now commercially available. EDI v2 focuses primarily on co-efficacy endpoints (PDAC stage shift in ENDPAC >0 group, and in all patients, excluding non-consented patients); effectiveness evaluation becomes a secondary objective. This addresses the challenges of low consent rate (~25%) due to lack of awareness of connection between NOD and PDAC and low acceptance for a novel research screening modality. The analyses of primary endpoints were adjusted to accommodate potential over-diagnosis due to screening and imbalance between ENDPAC >0 and ENDPAC ≤0 groups due to low consent rate and likely imperfect enrichment by ENDPAC, when evaluating all patients. Electronic eligibility checks and consent shorten the recruitment time, a critical factor for stage shift due to rapid progression of PDAC. A pre-randomization screening pilot study is planned to enhance the post-randomization consent rate. Intervention to Control randomization ratio is changed to 2:1, allowing more rapid recruitment and, when factoring the consent rate, doubling the sample size of the observation arm. Through these innovations, EDI v2 maintains the full advantage of Zelen’s design that made the trial feasible in sample size and cost. Simulation studies demonstrate that our approach correctly controls the type-1 error and the trial has adequate statistical power. The EDI trial represents an innovative and contemporary approach to developing and refining an early detection strategy for pancreatic cancer. Citation Format: Ying-Qi Zhao, Suresh T. Chari, Anirban Maitra, Lynn M. Matrisian, Eva E. Shrader, Bechien U. Wu, Avinash Kambadakone, Barbara Kenner, Jo Ann S. Rinaudo, Sudhir Srivastava, Ying Huang, Ziding Feng. The Early Detection Initiative trial version 2: A platform trial to test novel approaches to pancreatic cancer screening in patients with new onset hyperglycemia and diabetes [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A028.