Title: Pneumonia Investigation Bundle to Guide Therapy for Hospitalised Community Acquired Pneumonia (PIB CAP Study)
Funder: Chief Scientist Office, Scotland

Abstract: Design: Pragmatic, multicentre, open randomised controlled trial Setting: 5 UK hospitals. Target population: Inclusion criteria are patients >=16 years old hospitalised with CAP+CURB65 score>=2; recruitment and PIBCAP result within 36 hours of first arrival to hospital. Exclusion criteria include: No capacity to consent and assent refused by personal consultee; inpatient >=36 hours; active malignancy; immunodeficiency; solid organ transplant; active treatment not appropriate; pulmonary fibrosis; COPD on domiciliary oxygen therapy; mechanical ventilation; end of life care. Health technology being assessed: utility of a pneumonia investigation bundle using fast multiplex real-time Polymerase Chain Reaction assays for 26 respiratory bacteria and viruses along with urine for Legionella Antigen test (using BinaxNOW®) to personalise antibiotic treatment within 36 hours of hospital admission. This bundle is being called “PIB CAP”. Control treatment: investigations and treatment per NICE Pneumonia guideline. Planned interventions- There will be 851 patients from 5 sites planned. Half will be randomised to management as per the NICE Pneumonia guideline and half with personalised treatment following PIB CAP investigations (admission throat swab, spontaneous sputum if available and urine for Legionella Antigen test). The group undergoing PIB CAP investigations will have standard antibiotic treatment as per NICE Pneumonia guideline, but will be personalised following PIB CAP results within 36 hours of hospital admission. Assessments- will be carried out at baseline, Days 7 (safety assessment) and 30 days (to assess recovery). Who will deliver the interventions: clinical care team supported by the research nurse. Timetable: 4 months- training and finalise approvals; 6 months pilot study; 35 months conducting the study; 6 months data analysis, writing the publication and reports; 1 month close of study and archiving. Planned recruitment: 5 per calendar month per site. Primary outcome: We will use the Desirability of Outcome Ranking (DOOR) to assess the efficacy and safety of PIB CAP therapy based on assessing A] day 30 clinical response and B] day 30 total antibiotics Defined Daily Dose (DDD) to ensure by narrowing antibiotics this does not lead to subsequent additional antibiotic use. What is the probability that a randomly selected participant will have a better DOOR if assigned to receive PIB CAP compared to standard treatment? Power calculation: A sample size of 358 in each group will have 90% power to detect a probability of 0.570 that an observation in the PIB CAP group is more than an observation in the standard care group using a Wilcoxon (Mann-Whitney) rank-sum test with a 5% two-sided significance level. To allow for potential dropouts this sample size will be increased to 400 per group [i.e. a 10% drop out rate].To incorporate a design with 4 equally spaced scheduled interim analyses increases the sample size to 851. Health economics: A cost-utility (CUA) evaluation will be undertaken following standard NICE reference case specifications. Cost-effectiveness analysis (CEA) of cost per DDD reduction (exposure to antibiotics) will also be presented. Both CUA and CEA will be assessed by 30 day within trial analysis and longer term economic modelling. Expertise in team: The team has expertise in pneumonia, microbiology, virology, statistics, health economics and a trial methodologist with full support from our experienced CTU.

Lay abstract: There is an international drive to simplify antibiotic treatments to stop side effects from antibiotics and to stop the development of superbugs. Pneumonia is an infection of the lung affecting 5 to 11 people out of 1,000 in the population. About 9 in 100 patients admitted to hospital die with pneumonia. Prompt and appropriate antibiotic treatment is needed to cure the pneumonia. International guidelines propose using 7 to 10 days combination antibiotic treatment for patients admitted with pneumonia based on expert opinion. There are a lack of studies that definitively answer the length of treatment that is needed or what antibiotics to prescribe. We have developed a modern molecular test (PIB CAP bundle) that can identify the cause of pneumonia in 87% of patients compared with 39% from traditional tests in the NHS. Our test is very quick having an answer within a few hours and is not affected by prior antibiotic treatment. A common problem when patients are admitted to hospital is that a large number of patients will already have had antibiotic therapy by their GPs which can limit the results from standard care pneumonia investigations. In addition, traditional methods to investigate pneumonia in the NHS take too long to give an answer and as the success rate of investigations is low, this does not provide clinicians with clinical confidence to either shorten treatment or to simplify antibiotics. We intend to carry out a study in five major centres in the UK (Edinburgh, Newcastle, Nottingham, Southampton and London). Our virology team will set up this modern test so it can be done at each centre and the Edinburgh centre will check a sample of tests from other centres to ensure quality control. We intend to study 851 patients admitted with pneumonia. We are planning to have an online randomisation system so we can decide which patients will have standard care management and which patients will have their antibiotic treatment guided by our molecular tests. This randomisation system will also adjust for the severity of pneumonia so the groups are matched. The main aim of the study is to determine if PIB CAP reduces the antibiotic burden with no negative effect on clinical outcome relative to usual care. We will also assess if personalised antibiotic therapy is cost-effective for implementation in the NHS relative to usual care. The main endpoint is assessing both the outcome from the pneumonia and the total antibiotic burden at 30days- 30d was chosen to prove that narrowing the antibiotics initially is safe and does not lead to subsequent additional antibiotic use. The trial methodologists and statistician has shown that with 851 patients (allowing a 10% dropout), we can detect a small difference between the two groups. It will also allow us to do regular assessments as the study progresses to assess the trial progress. The British Lung Foundation and Nottingham Pneumonia PPI group have reviewed the grant and given helpful feedback that has improved the application. Following study completion we would present the study at local, national and international meetings and publish the paper in a prestigious peer reviewed journal with Open Access. The British Lung Foundation have offered to disseminate the results.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION