Optimising Rotavirus Vaccine in Aboriginal Children (ORVAC)

The ORVAC Trial: A Phase IV, Double-blind, Randomised, Placebo-controlled Clinical Trial of a Third Scheduled Dose of RV1 Rotavirus Vaccine in Australian Indigenous Infants to Improve Protection Against Gastroenteritis

Australian Indigenous children, particularly those living in remote communities, suffer a disproportionately high burden of rotavirus gastroenteritis disease. Despite the introduction of rotavirus vaccine into the Northern Territory (NT) Immunisation Schedule in 2006, the rate of hospitalization for rotavirus in NT Aboriginal children < 5 years continues to be high, and the rate ratio of rotavirus hospitalisations for Indigenous versus non-Indigenous children has actually increased. The reasons for sub-optimal vaccine response are not completely understood, but both reduced vaccine immune responses and low vaccine coverage are likely to be important factors.

The purpose of this study is to determine if Aboriginal children who receive an additional dose of RV1 between the ages of 6 and 12 months, will have an increase anti-rotavirus serum IgA seroconversion and decreased medical presentations with gastroenteritis in the first three years of life, compared to those who receive placebo.

Study Overview

• Status: Active, not recruiting
• Conditions: Viral Gastroenteritis Due to Rotavirus
• Intervention / Treatment: Drug: Rotarix (RV1); Drug: Placebo

Detailed Description

Australian Indigenous children, particularly those living in remote communities, suffer a disproportionately high burden of rotavirus gastroenteritis disease. Despite the introduction of rotavirus vaccine into the Northern Territory (NT) Immunisation Schedule in 2006, the rate of hospitalization for rotavirus in NT Aboriginal children < 5 years continues to be high, and the rate ratio of rotavirus hospitalisations for Indigenous versus non-Indigenous children has actually increased. The reasons for sub-optimal vaccine response are not completely understood, but both reduced vaccine immune responses and low vaccine coverage are likely to be important factors.

This study will enrol Aboriginal infants aged 6 months to < 12 months old who have received one or two prior doses of RV1. The coprimary aim is to determine whether an oral dose of RV1 vaccine at age 6 months to less than 12 months, compared to placebo, results in an increase in the average time to medical attendance for gastroenteritis before age 36 months (co-primary endpoint 1), and/ or superior immune protection against rotavirus gastroenteritis assessed approximately 1 to 2 months after vaccination (co-primary endpoint 2), in Australian Indigenous children.

This is a phase IV, randomised, placebo-controlled Bayesian trial with two strata representing residency based on a standard geographical classification of remoteness. It has the following key features:

1. Double-blind, randomised, placebo-controlled trial;
2. The procedures for enrolment, intervention, end-point and analysis are based on the principles of pragmatic trial design;
3. Non-fixed sample size up to 1,000 participants based on Bayesian stopping rules;
4. Fixed 1:1 enrolment into the active and control arm throughout the trial;
5. Frequent interim analyses can result in the trial stopping early for futility or expected success.

• Study Type: Interventional
• Enrollment (Estimated): 1000
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Tom Snelling; Phone Number: 0401355389; Email: tom.snelling@telethonkids.org.au
• Study Contact Backup: Name: Nelly Newall; Email: nelly.newall@telethonkids.org.au

Study Locations

• Australia
  • Northern Territory
    • Darwin, Northern Territory, Australia, 0810
      • Menzies School of Health Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 1 year (Child)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Aged ≥ 6 months and < 12 months
• Identified as Aboriginal and/or Torres Strait Islander and/or South Sea Islander per attending legally responsible care-giver/parent.
• Have received either one or two prior doses of RV1 vaccination as confirmed by checking the immunisation register.
• Legally responsible care-giver/parent is willing for their infant to participate in the study and is aware of the requirements of the protocol.
• Legally responsible care-giver/parent is willing to allow other parties involved in the treatment of their child (including general practitioner, medical centre staff and any other medical professionals the child may be a patient of for the duration of the trial) to be notified of their participation in the trial and for participation in the trial to be recorded within the Northern Territory Immunisation Register.
• The legally responsible care-giver/parent is willing to allow the study team to obtain a vaccination history from Northern Territory Immunisation Register and/or the Australian Childhood Immunisation Register (ACIR) and/or local provider.
• The legally responsible care-giver/parent is willing to allow the study team to obtain a medical history from hospitalisation and laboratory databases, the disease notification register, the participant's electronic medical records and/or from the participant's primary care provider for the period from enrolment to age 36 months
• Informed consent for the infant's/child's participation in the study has been given by the legally responsible care-giver/parent

Exclusion Criteria:

Has any contraindication for RV1 vaccination including:

• Severe combined immunodeficiency, any history of intussusception, any history of hypersensitivity to any vaccine component, or an uncorrected gastrointestinal tract malformation, receipt of more than two weeks of immunosuppressant or immune modifying drugs, (e.g. prednisolone > 0.5mg/kg/day) within 28 days of enrolment, confirmed or suspected severe immunosuppressive or immunodeficient conditions, including human immunodeficiency virus (HIV) infection
• Receipt of any rotavirus vaccination other than RV1
• Receipt in the previous 3 months of any blood products including immunoglobulin
• Has received no prior doses or > two prior doses of RV1 vaccination
• Medical condition or treatment with medication which in the opinion of the clinic staff would make the child unsuitable for the trial
• Previously enrolled in the trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rotarix; Rotarix (RV1) vaccine, 1mL liquid suspension administered orally.	Drug: Rotarix (RV1); ROTARIX™ (RV1) is a live-attenuated human monovalent oral vaccine containing attenuated G1P[8] human rotavirus strain sponsored and distributed in Australia by GlaxoSmithKline Biologicals where it is licensed for the prevention of rotavirus gastroenteritis.; Other Names: ROTARIX™
Placebo Comparator: Placebo; Placebo liquid suspension manufactured to mimic Rotarix (RV1) vaccine, 1ml administered orally	Drug: Placebo; The placebo for this trial will be Viscosweet, a clear and flavoured solution used as a pharmaceutical excipient repackaged into a labelled syringe identical to the active and firmly sealed with an end cap.; Other Names: Viscosweet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time from randomisation to medical attendance for acute gastroenteritis or acute diarrhoea illness	Time from randomisation to medical attendance (hospitalisation, emergency department presentation, medical clinic presentation) for which the primary reason for presentation is presumed or confirmed acute gastroenteritis or acute diarrhoea illness between randomisation and age 36 months.	Randomisation to 36 months
Occurrence of anti-rotavirus IgA seroconversion	Anti-rotavirus IgA seroconversion, defined as serum anti-rotavirus IgA > 20U/ ml 28 to 55 days post RV1/placebo among infants with anti-rotavirus serum IgA < 20U/ ml before RV1/placebo, to be summarised as the proportion of all children per group.	28-55 Days post RV1/placebo administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time from randomisation to hospitalisation for acute gastroenteritis or acute diarrhoea illness	Time from randomisation to hospitalisation for which the primary coded reason for admission is presumed or confirmed acute gastroenteritis or acute diarrhoea illness between randomisation and age 36 months.	Randomisation to 36 months
Time from randomisation to hospitalisation for rotavirus confirmed diarrhoea illness	Time from randomisation to hospitalisation for which rotavirus confirmed diarrhoea illness occurs between randomisation and age 36 months.	Randomisation to 36 months
Time from randomisation to Rotavirus infection	Time from randomisation to rotavirus infection meeting the jurisdictional case definition between randomisation and age 36 months.	Randomisation to 36 months
Change in anti-rotavirus IgA log titre between administration of intervention (RV1/placebo) and 28 to 55 days post dose	Change in anti-rotavirus IgA log titre between administration of intervention (RV1/placebo) and 28 to 55 days post dose, to be summarised as the proportion of all children per group.	Randomisation and 28-55 days post RV1/placebo administration
Occurrence of intussusception fulfilling Brighton criteria (see Appendix A)	The occurrence of intussusception fulfilling Brighton criteria (see Appendix A) within the first 28 days after RV1/placebo administration, to be summarised as the proportion of all children per group.	Within the first 28 days of RV1/placebo administration
Occurrence of a serious adverse event	Serious adverse events between randomisation and age 36 months, to be summarised as the proportion of all children per group.	Randomisation to 36 months
Medical attendance for confirmed acute gastroenteritis or acute diarrhoea illness between randomisation and 36 months gastroenteritis or acute diarrhoea illness.	Medical attendance (hospitalisation, emergency department presentations, medical clinic presentations) from the time of randomisation to age 36 months, for which the primary reason for presentation is presumed or confirmed acute gastroenteritis or acute diarrhoea illness, to be summarised as the proportion of all children per group.	Randomisation to 36 months

Collaborators and Investigators

• Sponsor: Telethon Kids Institute
• Collaborators: Menzies School of Health Research
• Investigators: Principal Investigator: Tom Snelling, Telethon Kids Institute

Publications and helpful links

General Publications

• Middleton BF, Danchin M, Jones MA, Leach AJ, Cunliffe N, Kirkwood CD, Carapetis J, Gallagher S, Kirkham LA, Granland C, McNeal M, Marsh JA, Waddington CS, Snelling TL. Immunogenicity of a Third Scheduled Dose of Rotarix in Australian Indigenous Infants: A Phase IV, Double-blind, Randomized, Placebo-Controlled Clinical Trial. J Infect Dis. 2022 Nov 1;226(9):1537-1544. doi: 10.1093/infdis/jiac038.
• Jones MA, Graves T, Middleton B, Totterdell J, Snelling TL, Marsh JA. The ORVAC trial: 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: a statistical analysis plan. Trials. 2020 Aug 26;21(1):741. doi: 10.1186/s13063-020-04602-w.
• Middleton BF, Jones MA, Waddington CS, Danchin M, McCallum C, Gallagher S, Leach AJ, Andrews R, Kirkwood C, Cunliffe N, Carapetis J, Marsh JA, Snelling T. 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 Nov 14;9(11):e032549. doi: 10.1136/bmjopen-2019-032549.

Study record dates

Study Major Dates

• Study Start (Actual): March 27, 2018
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: October 19, 2016
• First Submitted That Met QC Criteria: October 19, 2016
• First Posted (Estimated): October 21, 2016

Study Record Updates

• Last Update Posted (Estimated): March 6, 2024
• Last Update Submitted That Met QC Criteria: March 5, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Vaccine; Diarrhoea; Rotavirus; Aboriginal
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis
• Other Study ID Numbers: CVID/2015-03

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: IPD (de-identified) may be shared with other research teams subject to approval of the statistical analysis plan, data transfer agreement and appropriate ethics. However, prior approvals may be required from lead ethics
• IPD Sharing Time Frame: post publication of study results
• IPD Sharing Access Criteria: Researchers need to supply a statistical analysis plan and appropriate Ethics approvals
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No