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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
  1. Bianca Fleur Middleton1,
  2. Mark A Jones2,
  3. Claire S Waddington2,3,
  4. Margaret Danchin4,5,
  5. Carly McCallum2,
  6. Sarah Gallagher1,
  7. Amanda Jane Leach6,
  8. Ross Andrews7,
  9. Carl Kirkwood8,
  10. Nigel Cunliffe9,
  11. Jonathan Carapetis2,10,
  12. Julie A Marsh2,
  13. Tom Snelling2
  1. 1Global and Tropical Health Division, Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia
  2. 2Wesfarmers Centre of Vaccines and Infectious Diseases, Telethon Kids Institute, West Perth, Western Australia, Australia
  3. 3Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK
  4. 4Vaccine and Immunisation Research Group, Murdoch Childrens Research Institute, Parkville, Victoria, Australia
  5. 5Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
  6. 6Child Health Division, Menzies School of Health Research, Charles Darwin Univesity, Darwin, Northern Territory, Australia
  7. 7Global and Tropical Health Division, Menzies School of Health Research, Charles Darwin University, Brisbane, Queensland, Australia
  8. 8Enteric and Diarrheal Diseases, Bill and Melinda Gates Foundation, Seattle, Washington, USA
  9. 9Clinical Infection, Microbiology and Immunology, University of Liverpool, Liverpool, UK
  10. 10Faculty of Health and Medical Sciences, Centre for Child Health Research, University of Western Australia, Crawley, Western Australia, Australia
  1. Correspondence to Dr Bianca Fleur Middleton; bianca.middleton{at}menzies.edu.au

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 significant 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 significantly 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-confirmed gastroenteritis/diarrhoea, and rotavirus notification. 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 modifications to this protocol will be updated.

Trial registration number NCT02941107; Pre-results.

  • rotavirus
  • rotavirus vaccine
  • bayesian
  • northern territory
  • paediatric infectious disease & immunisation

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Footnotes

  • Contributors BFM, TS, MD and MAJ contributed to the preparation of the manuscript. BFM and TS developed the study processes and procedures and primarily authored the initial trial protocol. CM and SG have authored further protocol revisions. TS conceived the study and JAM devised the Bayesian approach, which was revised by MAJ. CSW, RA, CK, MD, NC JC and AJL contributed to the clinical aspects of the protocol. MD and JAM contributed to the study design. All authors have reviewed and approved the manuscript. All authors meet the BMJ uniform requirements for authorship inclusion and have seen and approved the final version of this manuscript.

  • Funding This work was supported by the National Health Medical Research Council (NHMRC) (1086952). BFM is supported by an NHMRC Postgraduate Scholarship (1134095), a RACP P&CHD NHMRC Scholarship and a Douglas and Lola Douglas Scholarship in Medical Science, Australian Academy of Science. TS is supported by an NHMRC Career Development Fellowship (1111657). MD is supported by a David Bickart Clinician Research Fellowship, University of Melbourne.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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