1 Middleton BF, et al. BMJ Open 2019;9:e032549. doi:10.1136/bmjopen-2019-032549 Open access The ORVAC trial protocol: a phase IV, double-blind, randomised, placebo- controlled clinical trial of a third scheduled dose of Rotarix rotavirus vaccine in Australian Indigenous infants to improve protection against gastroenteritis Bianca Fleur Middleton , 1 Mark A Jones , 2 Claire S Waddington, 2,3 Margaret Danchin, 4,5 Carly McCallum, 2 Sarah Gallagher, 1 Amanda Jane Leach, 6 Ross Andrews, 7 Carl Kirkwood, 8 Nigel Cunliffe, 9 Jonathan Carapetis, 2,10 Julie A Marsh, 2 Tom Snelling 2 To cite: Middleton BF, Jones MA, Waddington CS, et al. The ORVAC trial protocol: a phase IV, double-blind, randomised, placebo-controlled clinical trial of a third scheduled dose of Rotarix rotavirus vaccine in Australian Indigenous infants to improve protection against gastroenteritis. BMJ Open 2019;9:e032549. doi:10.1136/ bmjopen-2019-032549 ► Prepublication history and additional material for this paper are available online. To view these fles, please visit the journal online (http://dx.doi. org/10.1136/bmjopen-2019- 032549). Received 24 June 2019 Revised 17 September 2019 Accepted 15 October 2019 For numbered affliations see end of article. Correspondence to Dr Bianca Fleur Middleton; bianca.middleton@menzies. edu.au Protocol © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. Strengths and limitations of this study ► The ORVAC study is one of the frst studies to eval- uate both the immunological and the clinical impact of an additional dose of oral Rotarix rotavirus vac- cine administered to children between 6 and 12 months of age. ► This pragmatic randomised controlled trial is based on Bayesian adaptive design, an innovative trial de- sign that uses interim analyses to inform decisions about trial progression. ► While Bayesian adaptive trials are becoming in- creasingly common, they are yet to be established and accepted as routine research practice. ► The pragmatic trial design conducted under real- world conditions aims to increase the likelihood that a positive trial result will be more rapidly translated into policy and practice in the Northern Territory. ► This study will not be able to capture all cases of gastroenteritis following the administration of addi- tional dose Rotarix/placebo, only those presenting for clinical attendance; nor whether all cases of gas- troenteritis presenting for medical attendance are caused by rotavirus. ABSTRACT Introduction Rotavirus vaccines were introduced into the Australian National Immunisation Program in 2007. Despite this, Northern Territory Indigenous children continue to be hospitalised with rotavirus at a rate more than 20 times higher than non-Indigenous children in other Australian jurisdictions, with evidence of waning protection in the second year of life. We hypothesised that scheduling an additional (third) dose of oral human rotavirus vaccine (Rotarix, GlaxoSmithKline) for children aged 6 to <12 months would improve protection against clinically signifcant all-cause gastroenteritis. Methods and analysis This Bayesian adaptive clinical trial will investigate whether routinely scheduling an additional dose of Rotarix for Australian Indigenous children aged 6 to <12 months old confers signifcantly better protection against clinically important all-cause gastroenteritis than the current two-dose schedule at 2 and 4 months old. There are two coprimary endpoints: (1) seroconversion from baseline serum anti-rotavirus immunoglobulin A (IgA) titre <20 U/ mL prior to an additional dose of Rotarix/placebo to serum anti-rotavirus IgA titre >20 U/mL following the administration of the additional dose of Rotarix/placebo and (2) time from randomisation to medical attendance (up to age 36 months old) for which the primary reason is acute gastroenteritis/diarrhoea. Secondary endpoints include the change in anti-rotavirus IgA log titre, time to hospitalisation for all-cause diarrhoea and for rotavirus-confrmed gastroenteritis/diarrhoea, and rotavirus notifcation. Analysis will be based on Bayesian inference with adaptive sample size. Ethics, registration and dissemination Ethics approval has been granted by Central Australian Human Research Ethics Committee (HREC-16-426) and Human Research Ethics Committee of the Northern Territory Department of Health and Menzies School of Health Research (HREC-2016-2658). Study investigators will ensure the trial is conducted in accordance with the principles of the Declaration of Helsinki and with the ICH Guidelines for Good Clinical Practice. Individual participant consent will be obtained. Results will be disseminated via peer-reviewed publication. The trial is registered with Clinicaltrials.gov (NCT02941107) and important modifcations to this protocol will be updated. Trial registration number NCT02941107; Pre-results.