Prioritising and ranking methodological uncertainties in the design, conduct, and analysis of trials aiming to improve health outcomes for those living with multiple long-term conditions: A protocol for a modified Delphi study.

Introduction: Multiple long-term conditions (MLTCs), defined as the co-existence of two or more chronic health conditions, are increasingly prevalent across all age groups and disproportionately affect socioeconomically disadvantaged and ethnic minority populations. Trials targeting MLTCs face methodological challenges due to patient heterogeneity, variation in selection of conditions and limitations in design and analysis. These challenges may contribute to the lack of evidence to inform effective interventions for people with MLTCs. This study aims to systematically identify and prioritise key methodological uncertainties in the design, conduct and analysis of future trials aiming to improve health outcomes for people with MLTCs. Methods: We will conduct a four-round modified Delphi study involving key interest groups including methodologists, trialists, MLTC researchers, research funders, commissioners, regulators, people with MLTC lived experience and MLTC carers. The process will include two rounds of online questionnaires, one lived-experience meeting (in-person or virtual) and a final virtual consensus meeting. To promote inclusivity and diversity of input, participants may join at any stage. Responses from each round will be analysed and summarised to inform the next stage, with final priorities agreed through structured consensus voting. Expected Outcomes: This consensus study will produce a ranked list of methodological research uncertainties to guide future research and clinical trial design, conduct and analysis in MLTCs. Findings will be disseminated through a facilitated online dissemination workshop, academic channels and targeted public engagement activities to support inclusive and relevant MLTC research.