PROJECT SUMMARY/ABSTRACT Studies of cardiovascular disease increasingly embrace pragmatic clinical trials (PCT) to evaluate interventions under real-world conditions, often targeting under-resourced populations with high disease prevalence and disproportionate exposure to environmental risk factors, to generate data that may be more translatable and patient-centered than data from traditional randomized control trials. Community-based PCTs have several, morally-salient characteristics that raise novel and pressing ethical questions relating to researchers’ responsibilities and human protections. These studies are (1) often intentionally conducted in populations with high disease prevalence and limited available health care resources; (2) tend to impose upon, and extract value from, communities and community-based organizations that are socio-economically vulnerable; (3) occur outside the clinical setting, thereby positioning researchers in close physical proximity to participants or non- participants who could benefit from the research team’s knowledge, network, or clinical judgement. In turn, community-based PCTs prompt us to reconsider researcher responsibilities to not only protect from research-related harm but also to provide assistance or benefit to members of the community in which the study is conducted. There is a notable dearth of work attending to the ethics of PCTs conducted in community settings, which the proposed bioethics administrative supplement addresses by leveraging the study design and community relationships of the parent grant, AirPressureNYC (HL168597). The parent grant employs a sham PCT design to evaluate the effect of indoor portable air cleaners on blood pressure of New York City public housing residents with stable hypertension. Thus far ≥10% of individuals who directly interact with the research team through the screening process have been excluded from the study, most often because of asymptomatic hypertension above the inclusion criteria of 160/90 mmHg. The research teams’ ambivalence about how to manage their relationship to these individuals is what first motivated this line of inquiry. In the proposed supplement, we will empirically explore public and key stakeholder opinions on investigators’ obligations to members of communities engaged in PCTs, including study participants and non-participants, with specific focus on individuals excluded after screening. We will then conduct a normative analysis using the empirical data along with a thematic synthesis of the relevant literature to generate an ethical framework for characterizing and meeting these researcher obligations, directly informing guidance for PCT protocol development and oversight. This research will provide practicable directives for the ethical conduct of community based PCTs, specifically addressing NHLBI research priorities of confronting bioethical issues relevant to novel trial design and investigations involving vulnerable populations.