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.

Polypharmacy is associated with an increased risk of adverse patient outcomes across various settings, including inpatient care. To enhance the appropriateness of medication therapy management for patients during hospital stays, computerised interventions have shown promise with regard to patient safety. This study assesses whether the implementation of a clinical decision support system will optimise the process of inpatient medication therapy to prevent inappropriate medication use and thus promote patient safety.

The intervention will be evaluated in a prospective, cluster-randomised controlled trial using a stepped-wedge design. The study will be conducted in 12 hospitals across Germany over a total period of 33 months. Patients will be treated according to the group status of the hospital and receive either standard care or the Transsektorale Optimierung der Patientensicherheit or trans-sectoral optimisation of patient safety intervention. The primary outcome is the combined endpoint of all-cause mortality and all-cause hospitalisation. Secondary endpoints are, for example, inappropriate prescriptions, utilisation of different health services, cost-effectiveness, as well as patient-reported outcome measures. Parameters describing the attitudes of patients and healthcare professionals towards the intervention and organisational change processes will be collected as part of the process evaluation. The primary endpoint will be evaluated using hospital and outpatient claims data from participating statutory health insurances at the population level. There are multiple secondary endpoints with data linkage of primary and secondary data at study participant level. Statistical analysis will make use of (generalised) linear mixed models or generalised estimating equations, taking account of independent covariables. All data analyses of the process evaluation will be descriptive and explorative.

Data collection, storage and evaluation meet all applicable data protection regulations. The trial has been approved by the Ethics Committees of the University of Wuppertal and the Medical Association of Saarland, Germany. Results will be disseminated through workshops, peer-reviewed publications and local and international conferences.

DRKS00025485.