Probiotic to Reduce Infections iN CarE home Service userS (PRINCESS)

AIMS: To evaluate the effect of a dose of daily oral probiotics on cumulative systemic antibiotic administration days (CAAD) for all-cause, acute infections. HYPOTHESIS (Primary): Daily oral probiotic reduces CAAD for infection vs placebo in Care Home Resident (CHR). HYPOTHESIS (Mechanisms): Daily oral probiotic reduces gastrointestinal colonisation with AMR bacteria, enhances influenza vaccine response and modulates ex-vivo cytokine and chemokine response to Toll Like Receptor (TLR) agonists vs placebo in CHR. DESIGN: Double blind, individually randomised, 2 arm efficacy, placebo controlled trial. DURATION: 12 months. POPULATION: Care home residents in Wales and England. Inclusion: Currently living in a care home setting (residential, nursing or mixed); Participant is willing and able to give informed consent for participation in the trial OR if the participant lacks capacity, a consultee is willing to complete a consultee declaration form; Aged 65 years or older. Exclusion: The CHR may not enter the trial if ANY of the following apply: Is known to be immunocompromised (requiring immunosuppressants, long term, high dose oral, intramuscular or intravenous steroids); Is currently taking regular probiotics and is not willing to adapt to trial protocol; Currently participating in a clinical trial of an investigational medicinal product (CTIMP), or has been a participant in a CTIMP in the last thirty days; Is a temporary care home resident (i.e. less than 1 month of planned transitional/respite residential care); Death is thought to be imminent; Lactose intolerant. INTERVENTIONS: Probiotics containing Lactobacillus rhamnosus, LGG (LGG) and Bifidobacterium animalis subsp. lactis, BB-12 (BB-12) vs. placebo. PRIMARY OUTCOME: Primary: CAAD for all-cause infections over 12 months. SECONDARY OUTCOMES: Infection: Total number of days of antibiotic administration for each infection type (respiratory tract infection, urinary tract infection, gastrointestinal infection, unexplained fever and other); number, site, duration of infection; estimation of incidence and duration of diarrhoea and antibiotic-associated diarrhoea; Stool microbiology; C. difficile infection; Gram-negative Enterobacteriaceae and vancomycin resistant enterococci (VRE); LGG and BB-12; Oral Microbiology: Candida spp.; Health & Wellbeing: Self and/or proxy health-related quality of life EQ5D (5L); self-and/or proxy reported ICEpop CAPability measure for Older people; Hospitalisations: Number and duration of all-cause hospital stays; Mortality: Deaths; Mechanistic Immunology outcomes: Influenza vaccine efficacy (haemagglutination inhibition assay and antibody titres); full blood count and immune cell phenotypes, plasma cytokines and chemokines; cytokine and chemokine response in whole blood stimulated ex-vivo by toll-like receptor 2 and 4 agonists; monocyte and neutrophil phagocytosis of E.coli; serum Vitamin D. TERTIARY OUTCOME: Level of serum Vitamin D and AMR colonisation within stool sample. OTHER OUTCOME: Qualitative sub-study to understand how the trial was conducted within the care home context and identify the mechanisms which affect implementation of trial activities. ASSESSMENTS: Blood, saliva, stool samples collected at baseline, 3 month (no blood) and 12 month. Study nurses will attend regularly to record infections and antibiotic prescribing (MAR sheets). SAMPLE SIZE: Our previous study predicts 17.4 days on antibiotics/CHR/year. We aim to randomise between 258 and 270 participants. Assuming a mean number of days for which primary outcome data will be available (i.e. accounting for follow-up time and missing data) of approximately 250 days, this will provide at least 82% power to detect a 10% relative reduction in CAAD. RECRUITMENT: We will approach 660 residents from around 20 homes (assuming 50% CHR recruitment from homes with >50 eligible CHR). ANALYSIS: The primary analysis will be by intention-to-treat, and will consist of a be