BACKGROUND: Enhanced awareness of poor medication adherence could improve patient care. This article describes the original and adapted protocols of a randomized trial to improve medication adherence for cardiometabolic conditions. METHODS: The original protocol entailed a cluster randomized trial of 28 primary care clinics allocated to either (i) medication adherence enhanced chronic disease care clinical decision support (eCDC-CDS) integrated within the electronic health record (EHR) or (ii) usual care (non-enhanced CDC-CDS). Enhancements comprised (a) electronic interfaces printed for patients and clinicians at primary care encounters that encouraged discussion about specific medication adherence issues that were identified, and (b) pharmacist phone outreach. Study subjects were individuals who at an index visit were aged 18-74 years and not at evidence-based care goals for hypertension (HTN), diabetes mellitus (DM), or lipid management, along with low medication adherence (proportion of days covered [PDC] <80%) for a corresponding medication. The primary study outcomes were improved medication adherence and clinical outcomes (BP and A1C) at 12 months. Protocol adaptation became imperative in response to major implementation challenges: (a) the availability of EHR system-wide PDC calculations that superseded our ability to limit PDC adherence information solely to intervention clinics; (b) the unforeseen closure of pharmacies committed to conducting the pharmacist outreach; and (c) disruptions and clinic closures due to the Covid-19 pandemic. CONCLUSION: This manuscript details the protocol of a study to assess whether enhanced awareness of medication adherence issues in primary care settings could improve patient outcomes. The need for protocol adaptation arose in response to multiple implementation challenges.