Combined vascular endothelial growth factor/programmed death-ligand 1 blockade through atezolizumab/bevacizumab (A/B) is the current standard of care in advanced hepatocellular carcinoma (HCC). A/B substantially improved objective response rates compared with tyrosine kinase inhibitor sorafenib; however, a majority of patients will still not respond to A/B. Strong scientific rationale and emerging clinical data suggest that faecal microbiota transfer (FMT) may improve antitumour immune response on PD-(L)1 blockade. Early trials in melanoma with FMT and reinduction of immune checkpoint blockade (ICI) therapy in patients with anti-PD-1-refractory metastatic melanoma were reported in 2021 and demonstrated reinstatement of response to ICI therapy in many patients. Due to anatomical vicinity and the physiological relevance of the gut-liver axis, we hypothesise HCC to be a particularly attractive cancer entity to further assess a potential benefit of FMT in combination with ICI towards increased antitumour immunity. Additionally, HCC often occurs in patients with liver cirrhosis, where liver function is prognostically relevant. There is evidence that FMT may increase hepatic function and therefore could positively affect outcome in this patient population.

This prospective, multicentre, randomised, placebo-controlled, double-blind phase II clinical trial has been designed to assess immunogenicity and safety of FMT via INTESTIFIX 001 combined with A/B in advanced HCC in comparison to A/B with placebo. Primary endpoints are measured as tumour CD8+ T cell infiltration after 2 cycles of treatment with vancomycin, A/B+INTESTIFIX 001 in comparison to vancomycin-placebo, A/B+INTESTIFIX 001-placebo and safety of the therapeutic combination in advanced HCC. INTESTIFIX 001 is an encapsulated FMT preparation by healthy donors with a high alpha-diversity in their gut microbiome for oral administration, manufactured by the Cologne Microbiota Bank (CMB). Sample size was calculated to achieve a specific expected accuracy for the primary immunological endpoint. 48 subjects will be randomised to reach a goal of 42 usable measurements in the modified intention-to-treat set. Subjects will be randomised in a 2:1 ratio to A/B or placebo (28 A/B, 14 placebo).

The study was approved by ethics committee review and the German Federal Ministry of Drugs and Medical Devices. The trial is registered under EU CT no. 2023-506887-15-00. The outcome of the study will be disseminated via peer-reviewed publications and at international conferences.

NCT05690048.

Non-communicable diseases (NCDs), such as diabetes, cardiovascular diseases and cancer, are major global public health concerns. Diet quality—particularly the consumption of ultra-processed foods—has been associated with increased risk of NCDs. Traditional cohort studies are often expensive and logistically complex. The NutriNet-Brasil cohort leverages a web-based approach, offering a cost-effective and practical solution for comprehensive data collection and long-term follow-up.

Recruitments began in January 2020 through mass media, social media campaigns and collaborations with health organisations. Eligible participants are adults (aged ≥18 years) living in Brazil with internet access. Participants complete self-administered online questionnaires covering dietary intake, health status and other health determinants. Dietary assessment is based on the Nova classification system, which categorises foods by their level of processing.

Over 88 000 participants have completed the initial questionnaire. The cohort is predominantly women (79.9%) and highly educated (67.9% had completed higher education). The web-based design enabled the development and application of innovative dietary assessment tools, including the Nova24h and the Nova24hScreener, specifically designed to evaluate food processing levels. These tools have shown good performance in capturing dietary patterns and are central to the cohort’s aim. The online platform facilitates efficient recruitment, data collection and participant retention.

NutriNet-Brasil is pioneering the development of web-based cohort methodologies and instruments tailored to food processing research. Future work includes leveraging collaborations with national and international research centres to conduct multidisciplinary analyses and inform public health policies.