ABSTRACT Since the publication of To Err is Human in 1999, reductions in preventable harm have been slow. While pockets of excellence exist, national spread of proven safety interventions has been both incomplete and inconsistent. Contextual and implementation factors are widely recognized as root causes of this failure. Failed spread and scale-up of proven safety interventions wastes resources and misses a critical opportunity to reduce incalculable patient harm. As a result of these challenges, hospitals are increasingly joining quality improvement collaboratives (QICs). However, spread and scale up, within or outside of QICs, typically follow a “one size fits all” approach that does little to account for context because: (1) the critical contextual factors are not usually known before scaling up and (2) there is no other known model for scale-up. We have an opportunity to test a new model, using ‘NINJA’ as a model. Using routine surveillance, lab monitoring, and changes in medication regimens, Nephrotoxic Injury Negated by Just-In-Time Action (NINJA) reduced nephrotoxic medication related Acute Kidney Injury (NTMx-AKI) by 62% at one hospital. In a prospective multisite study, four hospitals did not reduce AKI at all while five reduced it by over 50%. Hospitals with a high rate of NTMx-AKI reduced it through one of two different implementation methods: (1) Including a pharmacy champion and multiple pharmacists working on NINJA or (2) Ensuring the NINJA team leader has no major competing demands drawing time away from implementation. We developed a prototype intervention (“CUSTOM NINJA”) that plans for and addresses the specific required contextual factors (e.g., pharmacy champion), selecting ONE of the TWO pathways to successful implementation. The proposed aims are to: 1.Test the usability, acceptability, and effectiveness of CUSTOM NINJA to plan for and address specific critical contextual factors and TWO different pathways for implementation. 2. Understand how context and facilitation of implementation affect variable reduction in AKI among CUSTOM NINJA hospitals, and compared to standard NINJA. 3. Assess the value of NINJA and CUSTOM NINJA implementation. Proposed methods combine time-series, statistical process control, interviews, surveys, retrospective and prospective cost assessments, and qualitative comparative analysis, which combines algebra with qualitative methods. The experienced study team has deep knowledge of patient safety and implementation, including scale-up through QICs. This study is set within the QIC Children’s Hospitals Solutions for Patient Safety, with more than 135 hospitals working together to eliminate preventable harm to children. The proposed study tests a scalable approach to overcome contextual and implementation barriers to more effectively and efficiently spread patient safety interventions nationally and internationally.