Title: 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
Funder: Department of Health and Social Care

Abstract: Acute Lymphoblastic Leukaemia (ALL) is one of the commonest forms of childhood cancer. Treatment has improved and survival rates are now high. ALL treatment involves chemotherapy which reduces the child’s ability to fight infections. Infection is now one of the commonest causes of death in children with ALL, and this is most likely to happen in the first five weeks of treatment – called “Induction”. _x000D_ _x000D_ In children with other types of leukaemia and in children whose ALL has come back after treatment (relapsed), it has been shown that giving a daily, low dose of antibiotics every day can reduce the risk of infection by about a half, but nobody has tested it in children the first time they have treatment for ALL._x000D_ _x000D_ A new research study to look at how best to treat childhood ALL called ALLTogether-1 will open soon. Our study, called CiproPAL, will work alongside the ALLTogether-1 study in the UK. CiproPAL will aim to answer the question “Does adding a daily, low-dose antibiotic (called ciprofloxacin) during the first part of chemotherapy treatment (induction) reduce the risk of infection in children, age 1-17 years old, with new ALL?”_x000D_ _x000D_ Each child who takes part in CiproPAL will receive either the antibiotic or no antibiotic – the decision will be made randomly by a computer. We will then look at whether they get infections._x000D_ _x000D_ Giving children regular antibiotics might change how well the infections respond to antibiotics in the future (“resistance”). We need to look at whether this happens on CiproPAL. We will do tests to see if the infections that make children unwell are more resistant to antibiotics, and whether the bacteria that usually live in us are more resistant to antibiotics. This will help to decide whether using ciprofloxacin is a good idea._x000D_ _x000D_ The tests to see if the infections that make children unwell are resistant will already be being done as part of the normal care of these children – we will just collect the information together. The test for bacteria that live in us is a sample of stool, or if the patient is finding it difficult to poo, a swab (a bit like cotton wool on a stick) that is rubbed onto the bottom. It does not hurt. The swab can be done by the patient, their carer, or a healthcare professional. It can be done when they are awake or when they are having an anaesthetic (for their other leukaemia treatment). We will ask for 5 of these samples to be done for each child over a year from when they join CiproPAL. These samples (of stool or swabs) will be optional – patients can still take part in CiproPAL whether they are done or not. All the patients and parents we’ve spoken to so far have said they would be willing to have swabs done as children with ALL often have swabs for other reasons and they aren’t a problem to do._x000D_ _x000D_ CiproPAL will also look at other possible effects of the antibiotic, including side effects, the amount of antibiotics children get (including for actual infections), and the costs of the different treatments (antibiotics or no antibiotics)._x000D_ _x000D_ To get the answer to the question about whether the regular antibiotics will reduce infections we need 1052 children to take part in CiproPAL, and this will take about 6 years from when we get funding. The information about resistance will take longer – until the end of the ALLTogether-1 study, in December 2031. We will tell researchers, healthcare professionals, and patients (and their families) about the results at each of these points.

Lay abstract: Background_x000D_ 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._x000D_ _x000D_ 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._x000D_ _x000D_ 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._x000D_ _x000D_ 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._x000D_ _x000D_ Aims and objectives_x000D_ 1. To assess efficacy of ciprofloxacin prophylaxis in reducing infection during the induction phase of the ALLTogether-1 Trial._x000D_ 2. To evaluate the impact of ciprofloxacin prophylaxis on AMR, both of invasive infections and colonising organisms._x000D_ _x000D_ Methods_x000D_ 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_x000D_ _x000D_ 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._x000D_ _x000D_ 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._x000D_ _x000D_ Timelines for delivery_x000D_ 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._x000D_ _x000D_ Anticipated impact and dissemination_x000D_ 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.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS;INFECTION