GSK Medicine: Study No.: Title: Rationale: Objectives: Indication: Study Investigators/ Centres: Research Methods: Data Source Study Design

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1 GSK Medicine: Rotarix (HRV1): GlaxoSmithKline (GSK) Biologicals oral live attenuated human rotavirus vaccine Study No.: (EPI-ROTA-025 VE AU DB) Title: A study on the impact of rotavirus vaccination on hospitalisations for rotavirus gastroenteritis in children aged <5 years in Australia. Rationale: The aim of the study was to assess the impact of HRV1 vaccine in all states of Australia in which the vaccine has been introduced and used widely, by monitoring trends in the incidence rates and duration of rotavirus gastroenteritis (RV GE) hospitalisations in children aged <5 years. This study also aimed to assess differences in the timeliness and compliance of vaccination, based on the RV vaccine administered. RotaTeq (HRV2): Merck & Co. s oral live pentavalent rotavirus vaccine. Objectives: Co-primary objectives: To monitor trend in the incidence rates and duration of hospitalisations for RV GE and all-cause GE, compared to bronchiolitis, in children <5 years of age by year, before and after rotavirus vaccine introduction* in all the states using HRV1 i.e. New South Wales (NSW), Tasmania (TAS), the Australian Capital Territory (ACT) and the Northern Territory (NT), both inside and outside rotavirus seasons**, from 1998 to * Rotavirus vaccines (HRV1 and HRV2) were both introduced in the Australian National Immunisation Program for the prevention of severe RV GE in May 2007 (HRV1 vaccine was launched in NT in October 2007). ** RV season in Australia is considered to be the colder months of June to November. To assess the timeliness and compliance of RV vaccination using data from the Australian Childhood Immunisation Register, comparing the 2-dose regimen of HRV1 vaccine (in NSW) with the 3-dose regimen of HRV2 vaccine (in Queensland [QLD]), from 2007 to Note: data were not collected in Tasmania as planned due to the low case numbers. The monitoring of the length of stay and severity of hospitalisations for all-cause GE and RV GE in children <5 years of age before and after vaccine introduction was not performed. The results obtained for NT were presented but were not interpreted as there were a lot of missing data. Indication: RV GE and all-cause GE Study Investigators/ Centres: GSK conducted study. Database study with no centres. Research Methods: Data Source: Existing computerised databases from the Australian Institute of Health and Welfare (AIHW). Australian Childhood Immunisation Register (ACIR) data for rotavirus vaccinations were provided by Medicare Australia (an Australian Government agency) through a special data request. Study Design: Ecological, database, self-contained study Study Population: - Children <5 years of age with a diagnosis of all-cause GE, RV GE or bronchiolitis* in the AIHW database in NSW, ACT, TAS and NT, from 1998 to 2009; - Children <5 years who were vaccinated with HRV1 or HRV2 vaccine in NSW and QLD, respectively, registered in the ACIR database in QLD and NSW, from 2007 to The subject information was de-identified and GSK Biologicals personnel were not able to make a link between the data and specific individuals; hence, no informed consent was to be obtained. * Hospitalisations for bronchiolitis were used as control disease. Study Exposures, Outcomes: Primary Outcomes: Occurrence of all-cause GE, RV GE and bronchiolitis in children <5 years by age group, state and year. Mean age of full immunisation of HRV1 and HRV2 vaccines in NSW and QLD. Percentage of full immunisation of HRV1 and HRV2 vaccines in NSW and QLD according to age-specific recommendations for RV immunisation in Australia and percentage outside age specific recommendations. Percentage of children immunised with the last dose of HRV1 vaccine according to age-specific recommendations for RV immunisation in Australia and percentage outside the age-specific recommendations in Australia. Percentage of children immunised with the last dose of HRV2 vaccine according to the age-specific recommendations for RV immunisation in Australia and percentage outside the age-specific recommendations. Secondary Outcomes: The primary and secondary outcome variables were not differentiated in the study protocol; hence they were all considered as primary in this CTRS Data Analysis Methods: Analyses were performed on the Total cohort, which included all subjects enrolled in the study. 1

2 The occurrence of all-cause GE, RV GE and bronchiolitis were analysed separately using time series analysis at baseline and post-vaccination for NSW, ACT and NT states. Compliance with age-specific national recommendations for HRV1 vaccine administration in children in NSW and HRV2 vaccine administration in children in QLD was tabulated. Descriptive statistics (Mean, Median, Mode and Maximum) of age were calculated for each dose of HRV1 and HRV2 vaccines, for children in NSW and in QLD, respectively. Limitations: None Study Results: Demographics/ Characteristics Not applicable Primary Outcome Measure: and post-vaccination incidence of GE hospitalisations in NSW, ACT and NT (Total Primary Outcome Measure: and post-vaccination incidence of RV GE hospitalisations in NSW, ACT and NT(Total

3 Primary Outcome Measure: and post-vaccination incidence of bronchiolitis cases in NSW, ACT and NT (Total Primary Outcome Measure: Child age in months at each dose HRV1 vaccine, NSW (Total * * Dose 1 Dose 2 Dose 1 Dose 2 Mode age Mean age

4 Median age Maximum age * Year of birth Primary Outcome Measure: Child age in months at each dose HRV2 vaccine, QLD (Total * * Dose 1 Dose 2 Dose 3 Dose 1 Dose 2 Dose 3 Mode age Mean age Median age Maximum age * Year of birth Primary Outcome Measure:.Compliance with age-specific national recommendations for HRV1 vaccine administration in infants in NSW, (Total Received 1st dose on or before 2 Received first Received 2nd dose on or before 4 Received second Number. of children 78,493 81,925 73,106 79,622 (born ) %* Number. of children 80,477 83,086 76,265 82,070 (born ) %* * Denominator was all children whether vaccinated or not. Compliance percentage calculated with the denominator including children registered as being vaccinated with HRV2 vaccine in NSW. Primary Outcome: Compliance with age-specific national recommendations for HRV2 vaccine administration in infants in QLD, (Total Received 1st dose by 2 Number of children (born ) Received first dose (any age) Received 2nd dose by 4 Received second dose (any age) Received 3rd dose by 6 Received third ,027 47,656 51,555 43,700 49,500 %* Number of children (born ) 52,710 53,784 49,912 53,270 46,150 51,169 %* * Denominator was all children whether vaccinated or not. Compliance percentages calculated with the denominator including children registered as being vaccinated with HRV1 vaccine in QLD. Primary Outcome: Timeliness of receiving each dose of HRV1 vaccine in NSW and HRV2 vaccine in QLD according to agespecific recommendations in children born (Total Dose 1 Dose 2 Dose 3 HRV1 - NSW Children born % 92% NA Children born % 93% NA HRV2 - QLD Children born % 92% 88% Children born % 94% 90% NA: Not Applicable Conclusion: Between July 2008 and June 2009, the incidence of RVGE (per 10,000 child/year) in children <1 year was 3.87 compared to at baseline in NSW, 8.4 compared to at baseline in ACT and compared to at baseline in NT. Over the same period, the incidence of GE (per 10,000 child/year) in children <1 year was compared to at baseline in NSW, compared to at baseline in ACT and compared to at baseline in NT. The incidence of bronchiolitis (per 10,000 child/year) in children <1 year was compared to at baseline in NSW, compared to at baseline in ACT and compared to at baseline in NT. 4

5 Similar results for were observed in all age groups (0-5 years) over the same period. For children born in , mean age for the 2-dose series administration of HRV1 vaccine was 1.5 months for Dose 1 and 3.8 months for Dose 2. For the 3-dose vaccine series administration of HRV2 vaccine, the mean age was 1.7 months for Dose 1, 3.8 months for Dose 2 and 6 months for Dose 3. In NSW, the proportion of all children receiving the second dose of HRV1 vaccine on or before 4 was 74.3% in and 77.9% in In QLD, the proportion of all children receiving the third dose of HRV2 vaccine on or before 6 was 68.9% in and 74.0% in The timeliness of receiving the first and second dose of HRV1 vaccine was 96% & 92% for children born in and 97% & 93% for children born in , respectively. The timeliness of receiving the second and third dose of HRV2 vaccine was 92% & 88% for children born in and 94% & 90% for children born in , respectively. Publications: None. Date updated: 16-Feb