Title: PEPtalk 2: Pilot of a randomised controlled trial to compare VZIG and aciclovir as post-exposure prophylaxis against chickenpox in children with cancer
Funder: Department of Health (England)

Abstract: 1. Background Primary varicella zoster virus (VZV) infection usually follows a benign clinical course and significant complications are uncommon in healthy children (1). By contrast, infection in the immunocompromised patient can result in significant morbidity and even mortality. Of the 1500 children diagnosed with cancer annually in the UK and Eire, over 25% lack immunity to VZV (2). In children with cancer, untreated varicella has a case fatality rate of 7% (3-4). Despite modern antiviral therapy, the disease continues to cause hospitalisation (including intensive care) and chemotherapy interruption among this group, as well as later shingles (5-7). Consequently, VZV exposure requires active management among susceptible children receiving treatment for cancer, by the provision of post-exposure prophylaxis (PEP) (8-10). There is wide variation in practice with respect to PEP in the UK, where the antiviral drug, aciclovir is often used as an oral alternative to the intramuscular injection of varicella zoster immune globulin (VZIG). Following favourable experiences during a period of VZIG shortage, UK paediatric oncologists were encouraged to consider aciclovir as an alternative to VZIG in widely consulted national guidance issued by the Royal College of Paediatrics & Child Health (RCPCH) (10). These treatments differ significantly in their mode of administration, cost and accessibility, yet their relative effectiveness in preventing varicella is unknown. As a result, opinion is divided among paediatric oncologists and both forms of PEP are in widespread use (2, 11). There are no controlled studies on the use of aciclovir as PEP in immunocompromised children. 2. Aims The primary objective of this pilot study is to assess the feasibility of a randomised controlled trial of aciclovir and VZIG as PEP in children with cancer. The secondary aims of the pilot study will be to explore families’ opinions on randomisation, assess the acceptability of each treatment arm, provide data to inform the sample size for the Phase III trial, collate data on symptomatic varicella and VZV seroconversion rates in trial participants and to obtain preliminary information to inform a formal cost-effectiveness comparison. 3. Plan of investigation This Phase II study is a multi-centre, randomised controlled trial. It is planned to recruit 50 children from 5 centres over a 12-month period. VZV-seronegative children will be randomised to receive either VZIG or aciclovir following significant exposure to varicella. Blood for VZV serology will be taken at the time of exposure and again 12 weeks later. For participants who develop chickenpox, further information on disease severity and health care usage will be collected. Patients and their families will be given a treatment diary to record their experiences which will include a short questionnaire (based on the child-friendly EQ-5D-Y) to collect information on quality of life. Information will be collected about the cost of each intervention. 4. Potential impact This pilot study will inform the design of a large-scale trial. This trial will aim to provide sound evidence on which form of PEP should be offered to protect children with cancer from chickenpox. If non-inferiority of aciclovir were to be shown then this would likely become the treatment of choice because it is expected to be less invasive, painful and distressing, when compared to the intramuscular injection of VZIG. Additionally, as aciclovir is the cheaper and more accessible form of PEP this may also provide significant benefits economically to the NHS. Finally, the results of such a trial may also inform the use of PEP in other high risk groups where similar uncertainties currently exist.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: CANCER AND NEOPLASMS;INFECTION