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

Abstract

IntroductionRotavirus 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 analysisThis 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 disseminationEthics 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.

Retrospective Case-Control Study of 2017 G2P[4] Rotavirus Epidemic in Rural and Remote Australia

“…It is plausible that administering an additional or booster dose of rotavirus vaccine to slightly older children (beyond manufacturer upper age limit restrictions) may extend protection into the second year of life. Scheduling a third dose of Rotarix vaccine (at between 6 and 11 months old) is currently under investigation in the NT [ 31 ].…”

Immunogenicity of a third scheduled dose of rotavirus vaccine in Australian Indigenous infants to improve protection against gastroenteritis: a phase IV, double-blind, randomised, placebo-controlled clinical trial

“…Both the study protocol and statistical analysis plan have been published. 12,13 Approvals were obtained from the NT Department of Health and Menzies School of Health Research Human Research Ethics Committee (2016-2658), and the Central Australian Human Research Ethics Committee . The protocol is registered on ClinicalTrials.gov (NCT02941107).…”

“…Laboratory procedures for measuring serum IgA to rotavirus have been detailed previously. 12,15,16 In brief, specific rotavirus IgA antibodies were measured by enzyme-linked immunoassays using rabbit anti-rotavirus polyclonal antisera as the coating antibody to capture a rotavirus lysate (G1P8) strain. Concentrations of rotavirus-specific IgA were measured in patient serum samples using a reference standard having been assigned a concentration of 1000 Arbitrary Units (U)/mL.…”

Vaccine success and challenges in northern Australia

“…The ORVAC study -Optimising Rotavirus Vaccine in Aboriginal Children, is an adaptive clinical trial that relaxes the upper age limit of rotavirus vaccine administration and administers a third 'booster dose' of oral Rotarix rotavirus vaccine to Northern Territory Aboriginal children aged 6-11 months. 11 This clinical trial -a partnership between the Menzies School of Health Research, Darwin and Telethon Kids Institute, Perth -has demonstrated that administering a booster dose of oral rotavirus vaccine improves the proportion of children with evidence of vaccine seroresponse (85% post third dose of Rotarix vs 72% post-placebo; ORVAC Stage 1; 2018-2020), 12 and continues to enrol children to evaluate the clinical impact -decreased medical presentations with gastroenteritis in the first 3 years of life (ORVAC Stage 2; 2022-2027). An early generation rotavirus vaccine, Rotashield, was associated with an increased risk of intussusception among infants aged >3 months.…”