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Abstract Background Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disease caused by inherited or de novo germline pathogenic variants in TP53. Individuals with LFS have a 70–100% lifetime risk of developing cancer. The current standard of care involves annual surveillance with whole-body and brain MRI (WB-MRI) and clinical review; however, there are no chemoprevention agents licensed for individuals with LFS. Preclinical studies in LFS murine models show that the anti-diabetic drug metformin is chemopreventive and, in a pilot intervention trial, short-term use of metformin was well-tolerated in adults with LFS. However, metformin’s mechanism of anticancer activity in this context is unclear. Methods Metformin in adults with Li-Fraumeni syndrome (MILI) is a Precision-Prevention phase II open-labelled unblinded randomised clinical trial in which 224 adults aged ≥ 16 years with LFS are randomised 1:1 to oral metformin (up to 2 mg daily) plus annual MRI surveillance or annual MRI surveillance alone for up to 5 years. The primary endpoint is to compare cumulative cancer-free survival up to 5 years (60 months) from randomisation between the intervention (metformin) and control (no metformin) arms. Secondary endpoints include a comparison of cumulative tumour-free survival at 5 years, overall survival at 5 years and clinical characteristics of emerging cancers between trial arms. Safety, toxicity and acceptability of metformin; impact of metformin on quality of life; and impact of baseline lifestyle risk factors on cancer incidence will be assessed. Exploratory end-points will evaluate the mechanism of action of metformin as a cancer preventative, identify biomarkers of response or carcinogenesis and assess WB-MRI performance as a diagnostic tool for detecting cancers in participants with LFS by assessing yield and diagnostic accuracy of WB-MRI. Discussion Alongside a parallel MILI study being conducted by collaborators at the National Cancer Institute (NCI), MILI is the first prevention trial to be conducted in this high-risk group. The MILI study provides a unique opportunity to evaluate the efficacy of metformin as a chemopreventive alongside exploring its mechanism of anticancer action and the biological process of mutated P53-driven tumourigenesis. Trial registration ISRCTN16699730. Registered on 28 November 2022. URL: https://www.isrctn.com/ EudraCT/CTIS number 2022-000165-41.

Abstract Background The Active Connected Engaged [ACE] study is a multi-centre, pragmatic, two-arm, parallel-group randomised controlled trial [RCT] with an internal pilot phase. The ACE study incorporates a multi-level mixed methods process evaluation including a systems mapping approach and an economic evaluation. ACE aims to test the effectiveness and cost-effectiveness of a peer-volunteer led active ageing intervention designed to support older adults at risk of mobility disability to become more physically and socially active within their communities and to reduce or reverse, the progression of functional limitations associated with ageing. Methods/design Community-dwelling, older adults aged 65 years and older (n = 515), at risk of mobility disability due to reduced lower limb physical functioning (Short Physical Performance Battery (SPPB) score of 4–9 inclusive) will be recruited. Participants will be randomised to receive either a minimal control intervention or ACE, a 6-month programme underpinned by behaviour change theory, whereby peer volunteers are paired with participants and offer them individually tailored support to engage them in local physical and social activities to improve lower limb mobility and increase their physical activity. Outcome data will be collected at baseline, 6, 12 and 18 months. The primary outcome analysis (difference in SPPB score at 18 months) will be undertaken blinded to group allocation. Primary comparative analyses will be on an intention-to-treat (ITT) basis with due emphasis placed on confidence intervals. Discussion ACE is the largest, pragmatic, community-based randomised controlled trial in the UK to target this high-risk segment of the older population by mobilising community resources (peer volunteers). A programme that can successfully engage this population in sufficient activity to improve strength, coordination, balance and social connections would have a major impact on sustaining health and independence. ACE is also the first study of its kind to conduct a full economic and comprehensive process evaluation of this type of community-based intervention. If effective and cost-effective, the ACE intervention has strong potential to be implemented widely in the UK and elsewhere. Trial registration ISRCTN, ISRCTN17660493. Registered on 30 September 2021. Trial Sponsor: University of Birmingham, Contact: Dr Birgit Whitman, Head of Research Governance and Integrity; Email: researchgovernance@contacts.bham.ac.uk. Protocol Version 5 22/07/22.

Abstract Background Anaemia in pregnancy remains prevalent in Nepal and causes severe adverse health outcomes. Methods This non-blinded cluster-randomised controlled trial in the plains of Nepal has two study arms: (1) Control: routine antenatal care (ANC); (2) Home visiting, iron supplementation, Participatory Learning and Action (PLA) groups, plus routine ANC. Participants, including women in 54 non-contiguous clusters (mean 2582; range 1299–4865 population) in Southern Kapilbastu district, are eligible if they consent to menstrual monitoring, are resident, married, aged 13–49 years and able to respond to questions. After 1–2 missed menses and a positive pregnancy test, consenting women

Abstract Background Surgeon and patient treatment preferences are important threats to the internal and external validity of surgical trials such as PROFHER, which compared surgical versus non-surgical treatment for displaced fractures of the proximal humerus in adults. We explored the treatment preferences expressed by surgeons and patients in the trial and how these impacted on patient selection, trial conduct and patient outcome. Methods A series of exploratory secondary analyses of the PROFHER trial data were undertaken. We reviewed the extent of surgeon and patient treatment preferences (surgery or not surgery) at screening (n = 1250) as well as prior preference (including no preference) of randomised patients (n = 250), and assessed their impact on recruitment and adherence to follow-up and rehabilitation. Changes in treatment after 2 years’ follow-up were explored. Patient preference and characteristics associated with trial inclusion or treatment preference (t test, chi-squared test, Wilcoxon rank-sum test) were included as treatment interaction terms in the primary trial analysis of shoulder functioning (Oxford Shoulder Score, OSS). Results Surgeons excluded 17% of otherwise eligible patients based on lack of equipoise; these patients had less complex fractures (p

Abstract Background Undernutrition causes around 3.1 million child deaths annually, around 45% of all child deaths. India has one of the highest proportions of maternal and child undernutrition globally. To accelerate reductions in undernutrition, nutrition-specific interventions need to be coupled with nutrition-sensitive programmes that tackle the underlying causes of undernutrition. This paper describes the planned economic evaluation of the UPAVAN trial, a four-arm, cluster randomised controlled trial that tests the nutritional and agricultural impacts of an innovative agriculture extension platform of women’s groups viewing videos on nutrition-sensitive agriculture practices, coupled with a nutrition-specific behaviour-change intervention of videos on nutrition, and a participatory learning and action approach. Methods The economic evaluation of the UPAVAN interventions will be conducted from a societal perspective, taking into account all costs incurred by the implementing agency (programme costs), community and health care providers, and participants and their households, and all measurable outcomes associated with the interventions. All direct and indirect costs, including time costs and donated goods, will be estimated. The economic evaluation will take the form of a cost-consequence analysis, comparing incremental costs and incremental changes in the outcomes of the interventions, compared with the status quo. Robustness of the results will be assessed through a series of sensitivity analyses. In addition, an analysis of the equity impact of the interventions will be conducted. Discussion Evidence on the cost and cost-effectiveness of nutrition-sensitive agriculture interventions is scarce. This limits understanding of the costs of rolling out or scaling up programs. The findings of this economic evaluation will provide useful information for different multisectoral stakeholders involved in the planning and implementation of nutrition-sensitive agriculture programmes. Trial registration ISRCTN65922679. Registered on 21 December 2016

Abstract Background Maternal and child undernutrition have adverse consequences for pregnancy outcomes and child morbidity and mortality, and they are associated with low educational attainment, economic productivity as an adult, and human wellbeing. ‘Nutrition-sensitive’ agriculture programs could tackle the underlying causes of undernutrition. Methods/design This study is a four-arm cluster randomised controlled trial in Odisha, India. Interventions are as follows: (1) an agricultural extension platform of women’s groups viewing and discussing videos on nutrition-sensitive agriculture (NSA) practices, and follow-up visits to women at home to encourage the adoption of new practices shown in the videos; (2) women’s groups viewing and discussing videos on NSA and nutrition-specific practices, with follow-up visits; and (3) women’s groups viewing and discussing videos on NSA and nutrition-specific practices combined with a cycle of Participatory Learning and Action meetings, with follow-up visits. All arms, including the control, receive basic nutrition training from government community frontline workers. Primary outcomes, assessed at baseline and 32 months after the start of the interventions, are (1) percentage of children aged 6–23 months consuming ≥ 4 out of 7 food groups per day and (2) mean body mass index (BMI) (kg/m2) of non-pregnant, non-postpartum (gave birth > 42 days ago) mothers or female primary caregivers of children aged 0–23 months. Secondary outcomes are percentage of mothers consuming ≥ 5 out of 10 food groups per day and percentage of children’s weight-for-height z-score 70%) proportion of Scheduled Tribe or Scheduled Caste (disadvantaged) households. A process evaluation will assess the quality of implementation and mechanisms behind the intervention effects. A cost-consequence analysis will compare incremental costs and outcomes of the interventions. Discussion This trial will contribute evidence on the impacts of NSA extension through participatory, low-cost, video-based approaches on maternal and child nutrition and on whether integration with nutrition-specific goals and enhanced participatory approaches can increase these impacts. Trial registration ISRCTN , ISRCTN65922679. Registered on 21 December 2016.