CiproPAL (Ciprofloxacin Prophylaxis in Acute Leukaemia): A randomised trial to assess the use of ciprofloxacin prophylaxis to prevent bacterial infection in children treated on the induction phase of the ALLTogether-1 treatment protocol

Background One third of all deaths of children with Acute Lymphoblastic Leukaemia (ALL) in the most recent UK trial were due to infection. The first phase of ALL treatment, induction, has the highest rate of infection (15% of patients) and infection-related mortality. Prophylactic fluroquinolone antibiotics reduce episodes of fever and documented infections in adults with acute leukaemia. There are no randomised trials evaluating prophylaxis in de novo paediatric ALL patients, though in more intensively treated acute myeloid leukaemia or relapsed ALL a trial showed halving the rates of bacteraemia (44% vs. 22%) with prophylaxis. Prophylaxis has not been associated with immediate harm, but may increase antimicrobial resistance (AMR) over time. Previous paediatric cohorts did not show any short term increase in AMR. The longer-term effects on AMR rates are unknown. With an 8-group, pan-European platform trial of ALL therapy (ALLTogether-1) commencing there is a unique opportunity to cost-effectively study the use of prophylactic fluoroquinolones in this population. Aims and objectives 1. To assess efficacy of ciprofloxacin prophylaxis in reducing infection during the induction phase of the ALLTogether-1 Trial. 2. To evaluate the impact of ciprofloxacin prophylaxis on AMR, both of invasive infections and colonising organisms. Methods Multi-centre randomised trial of prophylactic ciprofloxacin (10mg/kg BD, enteral/IV) versus standard of care during the neutropenic period of induction with internal pilot study in patients aged 1-17 years with de-novo ALL treated on ALLTogether-1. Exclusion criteria include: patients with Down syndrome (who already receive ciprofloxacin prophylaxis), contraindication to fluoroquinolones, non-consent to ALLTogether-1 or CiproPAL. AMR of colonising organisms will be assessed with stool or peri-rectal swab cultures performed at five timepoints within the first year. Longer term invasive infection AMR monitoring will include sensitivity testing of all organisms isolated in confirmed infection for the duration of ALLTogether-1 The primary outcome is rate of sterile site bacterial infections during induction, evaluated by intention to treat analysis. Secondary outcomes include rates of febrile episodes, febrile neutropenia, severe infection and infection-related death; rates of AMR; antibiotic exposure; secondary infections; and quinolone side effects. A model-based health economic analysis will be undertaken. Using a conservative effect estimate of 40% reduction in bacteraemia (i.e. a reduction from 15% to 9%) 1052 patients randomised 1:1 gives 85% power with a 5% 2-sided alpha. Timelines for delivery We anticipate 12 months to finalise the protocol, obtain relevant REC, competent authority and study site approvals. CiproPAL requires 42 months recruitment with a pilot phase of 12 months and 12 months active follow-up per child with ongoing AMR monitoring until the end of ALLTogether-1 (estimated December 2031). The total time from funding allocation to end of trial is 133 months, with the CiproPAL primary outcome reporting during year 6. Anticipated impact and dissemination Dissemination will be through academic outputs (papers, presentations, and reports) and connections with charities, patient and parent organisations, and international guideline groups. CiproPAL may change the management of children and young people with ALL across the UK and globally.