Oral Nitazoxanide in Acute Gastroenteritis in Australian Indigenous Children

This is a multi-centre (RDH and ASH), phase IV, double-blind, randomised, placebo-controlled Bayesian adaptive trial of oral NTZ for the treatment of acute gastroenteritis requiring admission to hospital. A maximum of 300 children aged between three months and less than five years of age will be enrolled. Study participation is from the point of enrolment until 60 days after enrolment. Enrolment will occur within 48 hours of admission to hospital. Enrolled participants will be randomised 1:1 to Nitazoxanide (NTZ) or placebo. Other treatment and management will be as per the standard of care described in the admitting hospital's guidelines and will be ultimately the decision and responsibility of the named medical consultant. Stool samples will be collected at the point of admission. Solicitation of symptoms will be by review of routinely collected medical data recorded in the participant's medical record, and will be supplemented by completion of study specific diary cards until discharge (for the first 210 enrolments). Attempts will be made to contact participants at day 7 after enrolment (by telephone if already discharged) to ascertain symptoms occurring in the intervening period. At days 30 and 60 (for first 210 enrolments ) and Day 60 (for enrolment #211 onwards) after enrolment a clinical record review will be conducted for all participants to ascertain health care attendances following discharge.

The sample size for the study is a maximum of 300 children, randomised on a 1:1 basis to the two study treatment groups. The trial will stop recruiting when pre-specified decision criteria are met based on treatment superiority or trial futility or when 300 children have been enrolled. Based on previously published data it is hypothesised that NTZ treatment will result in a decrease in the median duration of medically significant illness by 1 day. A decrease of one day is considered to be the minimum useful decrease of relevance to the study setting. It is anticipated that there will be minimal lost to follow-up as the primary endpoint will be available for the majority of participants in each arm due to the short interval between enrolment and meeting the criteria for the primary endpoint.

The trial will be conducted as a fixed allocation Bayesian adaptive randomised controlled trial. This statistical methods in the protocol are written to be practical and accessible to individuals with an understanding of common clinical trial designs and classical frequentist analytical methods but without training in Bayesian statistics. A formal description of the interim Bayesian data analysis fundamental to this design, which assumes substantial familiarity with Bayesian calculation of posterior distributions conditioned on observed data, is documented in the Statistical Analysis Plan. There is overlap between the protocol and statistical analysis plan so that each may serve an appropriate audience as a standalone description of the statistical methods. Briefly, within the Bayesian framework, the intervention arms are evaluated and sequential Bayesian statistical analyses are used over time to incorporate new trial outcome information to determine if a treatment is superior, inferior, or equivalent, with respect to the primary end-point. Every child will be randomly assigned in a ratio 1:1 to placebo or nitazoxanide. Children will be classified by membership in different strata, where membership will be defined by age and geographical region. Whenever an interim analysis reports superiority, inferiority, or equivalence with respect to the primary end-point this is termed a Statistical Trigger. At any given interim analysis, a Statistical Trigger may be reached for all children or for one or more strata.