Clinical trial NCT02941107: Optimising Rotavirus Vaccine in Aboriginal Children
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE4
Conditions: Viral Gastroenteritis Due to Rotavirus
Keywords: Aboriginal
Rotavirus
Vaccine
Diarrhoea
Lead sponsor: Telethon Kids Institute
Sponsor class: OTHER
Collaborators: name: Menzies School of Health Research
First posted: 2016-10-21
Enrollment: 1000
Sex: ALL
Minimum age (years): 6
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Time from randomisation to medical attendance for acute gastroenteritis or acute diarrhoea illness
timeFrame: Randomisation to 36 months
measure: Occurrence of anti-rotavirus IgA seroconversion
timeFrame: 28-55 Days post RV1/placebo administration
Secondary outcomes:
measure: Time from randomisation to hospitalisation for acute gastroenteritis or acute diarrhoea illness
timeFrame: Randomisation to 36 months
measure: Time from randomisation to hospitalisation for rotavirus confirmed diarrhoea illness
timeFrame: Randomisation to 36 months
measure: Time from randomisation to Rotavirus infection
timeFrame: Randomisation to 36 months
measure: Change in anti-rotavirus IgA log titre between administration of intervention (RV1/placebo) and 28 to 55 days post dose
timeFrame: Randomisation and 28-55 days post RV1/placebo administration
measure: Occurrence of intussusception fulfilling Brighton criteria (see Appendix A)
timeFrame: Within the first 28 days of RV1/placebo administration
measure: Occurrence of a serious adverse event
timeFrame: Randomisation to 36 months
measure: Medical attendance for confirmed acute gastroenteritis or acute diarrhoea illness between randomisation and 36 months gastroenteritis or acute diarrhoea illness.
timeFrame: Randomisation to 36 months
Other outcomes:
Locations:
city: Darwin
country: Australia
facility: Menzies School of Health Research
state: Northern Territory
Study officials:
affiliation: Telethon Kids Institute
name: Tom Snelling
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.