GSK Medicine: Rotarix (HRV): GlaxoSmithKline Biologicals live attenuated human rotavirus vaccine Study No.: (EPI-ROTA ) Title:

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1 GSK Medicine: Rotarix (HRV): GlaxoSmithKline Biologicals live attenuated human rotavirus Study No.: (EPI-ROTA ) Title: Case-control study to evaluate the effectiveness of GlaxoSmithKline (GSK) Biologicals live attenuated human rotavirus (HRV) (Rotarix ) against community-acquired rotavirus severe gastroenteritis (RV SGE) among hospitalised children born after 1 October 2006, in Belgium. Rationale: The aim of this study was to assess HRV effectiveness in preventing community-acquired RV SGE among hospitalised infants, in Belgium. The population in this study was limited to children born after 01 October 2006 and at least 14 weeks of age. Baseline data on the proportion of hospital admissions due to RV SGE and co-infections with other organisms were also estimated. Data were also collected from subjects who received Rotateq. Rotateq (Rota): Merck & Co.,Inc. s pentavalent rotavirus Objectives: Primary objective: To estimate the effectiveness of HRV full series (2 doses) in preventing community-acquired RV SGE among hospitalised children born after 01 October 2006 and at least 14 weeks of age. Secondary objectives: To estimate the effectiveness of HRV full series (2 doses) in preventing community-acquired RV SGE by age-groups (3-6 months, 7-12 months, months, > 25 months of age) among hospitalised children born after 01 October 2006 and at least 14 weeks of age. To estimate the effectiveness of HRV when used in typical real-life situations (at least 1 dose i.e. 1 or 2 doses) in preventing community-acquired RV SGE among hospitalised children born after 01 October 2006 and at least 14 weeks of age. To estimate the effectiveness of rotavirus s (HRV or Rota s) when used in typical real-life situations (at least 1 dose i.e. 1, 2 or 3 doses) in preventing community-acquired RV SGE among hospitalised children born after 01 October 2006 and at least 14 weeks of age. In order to estimate the overall burden of disease due to RV SGE, co-infection with other organisms and distribution of RV type in the study subjects during the study period, the following secondary study objectives were also considered: To estimate the proportion of RV SGE admissions in children born after 01 October 2006 and at least 14 weeks of age. To estimate the proportion of RV SGE hospitalisations co-infected with other organisms (Astrovirus, Norovirus, Adenovirus) among children born after 01 October 2006 and at least 14 weeks of age. To determine the distribution of RV SGE hospital admissions by the age of the child, month of year and RV type, among hospitalised children born after 01 October 2006 and at least 14 weeks of age. Indication: Prevention of community-acquired RV SGE in infants aged at least 14 weeks. Study Investigators/Centres: GSK conducted study in 39 centres across Belgium. Only 32 of the centres enrolled subjects. Research Methods: Data Source: Parents/guardians interview, review of medical records and cards, stool sampling Study Design: Hospital-based, multi-centre, matched (by hospital and age), case-control study. Study Population: - Enrolled cases included all children born after 01 October 2006, at least 14 weeks of age (minimum age at which both doses of HRV should have been administered along with 2 weeks for the development of immunity), and hospitalised for SGE at the study hospitals during the designated study period of at least one year. - Probable cases included those children who were born after 01 October 2006, at least 14 weeks of age, hospitalised for SGE in the study hospitals and whose stool samples had been tested positive for RV by a rapid test at the bedside or hospital laboratory. - Confirmed cases included those children who were born after 01 October 2006, at least 14 weeks of age, hospitalised for SGE in the study hospitals and whose stool samples had been tested positive for RV by polymerase chain reaction (PCR) at the GSK designated laboratory. For each probable case, one control hospitalised or visiting the hospital outpatient clinic for non-ge causes in the same study hospital, during the same time period as the case, was included after matching by age (up to a maximum of ± 6 weeks from the date of birth of the case). Informed consent was sought from parents/guardians of all eligible cases. Study Exposures, Outcomes: The study groups were as follows: - Cases Group: Subjects born after 01 October 2006, at least 14 weeks of age and hospitalised for SGE (see the definitions of enrolled, probable and confirmed cases in the Study Population section). - Controls Group: Subjects matched by age with the cases, hospitalised or visiting the hospital outpatient clinic for

2 non-ge causes in the same study hospital, during the same time period. Primary outcome Occurrence of PCR-confirmed RV SGE (> 14 days after receipt of ) in children fully vaccinated with HRV or in unvaccinated children. Secondary outcomes Occurrence of PCR-confirmed RV SGE (> 14 days after receipt of ) in children who received one or two doses of HRV or in unvaccinated children. Occurrence of PCR-confirmed RV SGE (>14 days after receipt of ) in children who received at least one dose of HRV or Rota s or in unvaccinated children. Following outcomes needed to estimate the burden of RV SGE, co-infection with other organisms and RV strain distribution in study subjects: Occurrence of SGE due to RV among children born after 01 October 2006, at least 14 weeks of age and admitted to hospital. Occurrence of co-infections with other organisms (Astrovirus, Norovirus and Adenovirus) among children born after 1 October 2006, at least 14 weeks of age and hospitalized with PCR-confirmed RV SGE. Occurrence of PCR-confirmed RV SGE by age and month of year, among children born after 01 October 2006, at least 14 weeks of age and admitted to the hospital. Occurrence of RV types among hospitalized PCR-confirmed RV SGE children born after 01 October 2006 and at least 14 weeks of age. Data Analysis Methods: Analyses were performed on the Total screened cases cohort, the Total enrolled cohort, the According-To-Protocol (ATP) enrolled cohort and the ATP confirmed cohort. - The Total screened cases cohort included all children born after 01 October 2006 and at least 14 weeks of age, who were admitted to the hospital for symptoms of SGE. - The Total enrolled cohort included all subjects (cases and controls) enrolled in the study. - The ATP enrolled cohort included all valid enrolled cases and controls (i.e. those meeting all eligibility criteria and complying with the procedures defined in the protocol). Cases may not have had any control in this cohort (e.g. for not probable cases, no controls were looked for; controls may not have been found etc). However, controls with no eligible cases were eliminated from this cohort. - The ATP confirmed cohort included all valid confirmed cases (i.e. those meeting all eligibility criteria and complying with the procedures defined in the protocol) and their matched controls. Confirmed cases without matched controls were eliminated from this cohort. Vaccine effectiveness () analysis Vaccine effectiveness was calculated as 1 minus the matched odds ratio multiplied by 100%. Matched odds ratios for were calculated as the hazard ratio by using the conditional logistic regression, with associated p-values and 95% confidence intervals. The was evaluated in the following circumstances: 1. Fully vaccinated with HRV against unvaccinated (overall and by age classes). 2. Fully or partially vaccinated with HRV against unvaccinated. 3. Fully or partially vaccinated with HRV or Rota s against unvaccinated. All s were estimated on one hand with pairs for which the case and control(s) had a validated source of history and on the other hand including all pairs (whatever the source of ). Note: Only confirmed cases and their respective controls (if at least one valid control) were taken. Finally, a sensitivity analysis was conducted by including subjects whose status was other or for s 1 or 2 and for 3. This status could be determined with assumptions that these subjects were and were not vaccinated (Sensitivity +: cases and controls were assumed respectively ; Sensitivity -: cases and controls were assumed respectively ). Burden of disease analysis The proportion of SGE hospitalisations attributable to RV was computed with 95% confidence interval (CI) and was also cross-tabulated with co-infection as the proportion of SGE hospitalisations attributable to Rapid test positive SGE, the proportion of Rapid test positive SGE hospitalisations attributable to PCR positive RV and the proportion of PCR positive RV SGE hospitalisations attributable to co-infected RV. The distribution of cases by year and month of hospitalisations and the distribution of rotavirus genotypes by age groups were also tabulated. Limitations: Not applicable

3 Study Results: Demographics/Baseline Characteristics Cases Group Controls Group N (Total enrolled cohort ) Females:Males* 143: :188 Mean Age, Months (SD) 13.0 (7.26) 16.7 (7.97) *Note: Gender was missing for 246 subjects in the Cases Group and 12 subjects in the Controls Group. Primary outcome: Effectiveness of HRV full series (ATP confirmed cohort) Number of Cases Number of Controls 95%CI Fully HRV Fully HRV LL UL All sources Validated Sensitivity Number of Cases Number of Controls Fully HRV Other or Fully HRV Other or Sens.+ Sens.- All sources Validated Note: Fully HRV means 2 doses of HRV All sources for Sensitivity: rotavirus vaccinated status of the case and the matched control are fully HRV vaccinated, not vaccinated, or other. All sources for : rotavirus vaccinated status of the case and the matched control are fully HRV vaccinated or not vaccinated. Validated: Only validated sources, meaning that in addition, sources of the case and of the matched control must be validated. Sens.+ = Sensitivity +: cases and controls with other or rotavirus status are assumed respectively Sens. - = Sensitivity -: cases and controls with other or rotavirus status are assumed respectively Secondary outcome: Effectiveness of HRV full series by age group of the case (ATP confirmed cohort) Number of Cases Number of Controls 95%CI Sensitivity Age Fully HRV Fully HRV LL UL Sens. + Sens. - (months) All sources Validated = Between 3 and 6 months of age (6 not included) 6-11 = Between 6 and 12 months of age (12 not included) = Between 12 and 24 months of age (24 not included) 24+ = More than 24 months of age (24 included) Note: Fully HRV means 2 doses of HRV All sources for Sensitivity: rotavirus vaccinated status of the case and the matched control are fully HRV, not vaccinated, or other. All sources for : rotavirus vaccinated status of the case and the matched control are fully HRV vaccinated or not vaccinated. Validated: Only validated sources meaning that in addition, sources of the case and of the matched control must be validated.

4 Sens.+ = Sensitivity +: cases and controls with other or rotavirus status are assumed respectively Sens. - = Sensitivity -: cases and controls with other or rotavirus status are assumed respectively Note: For 3-5 and 24+ age classes, not enough cases and controls were enrolled as per the inclusion/ exclusion criteria. Secondary outcome: Effectiveness of HRV partial or full (intention to vaccinate analysis) series (ATP confirmed cohort) Number of Cases Number of Controls 95%CI HRV HRV All sources Validated Sensitivity Partial or full HRV Number of Cases Other or Partial or full HRV Number of Controls Other or LL UL Sens. + Sens. - All sources Validated Note: Partial/full HRV means at least 1 dose of HRV. All sources for Sensitivity: rotavirus vaccinated status of the case and the matched control are fully or partially HRV vaccinated, not vaccinated, or other. All sources for : rotavirus vaccinated status of the case and the matched control are fully or partially HRV vaccinated or not vaccinated. Validated: Only validated sources meaning that in addition, sources of the case and of the matched control must be validated. Sens.+ = Sensitivity +: cases and controls with other or rotavirus status are assumed respectively Sens. - = Sensitivity -: cases and controls with other or rotavirus status are assumed respectively Secondary outcome: Effectiveness of rotavirus s partial or full series (ATP confirmed cohort) Number of Cases Number of Controls 95%CI All sources Validated Sensitivity Partial or full Number of Cases Other or Number of Controls Other or LL UL Sens. + Sens. - All sources Validated Note: Partial/full vaccinated means at least 1 dose of rotavirus. All sources for Sensitivity: all matched case and control. All sources for : case and matched control with at least one of both rotavirus status set to or other are not part from the analysis. Validated: Only validated sources meaning that in addition, sources of the case and of the matched control must be validated. Sens.+ = Sensitivity +: cases and controls with other or rotavirus status are assumed respectively

5 Sens. - = Sensitivity -: cases and controls with other or rotavirus status are assumed respectively Secondary outcome: Proportion of SGE hospitalisations attributable to Rapid test positive SGE (Total screened cases cohort (aggregated logbook)) Number of RV SGE Number of SGE hosp. Proportion LL UL hosp. with Rapid test Note: Number of SGE hosp. and RV SGE are computed from the aggregated logbook. No consistency checks have been done between the aggregated logbook and the initial logbook. LL, UL = 95% Lower and Upper exact confidence limits Secondary outcome: Proportion of Rapid test positive SGE hospitalisations attributable to PCR+ RV (ATP enrolled cohort) Number of PCR+ RV SGE hosp. Number of RV SGE hosp. with Rapid test Proportion LL UL Sens + Sens LL, UL = 95% Lower and Upper exact confidence limits Sens + = Sensitivity +: cases with PCR result are assumed RV SGE Sens - = Sensitivity -: cases with PCR result are assumed SGE not RV Secondary outcome: Proportion of PCR+ RV SGE hospitalisations attributable to co-infected RV (ATP enrolled cohort) Co-infection Number of SGE hosp. due to RV / RV coinfection Number of PCR+ RV SGE hosp. Proportion None (only RV) Astrovirus Norovirus Adenovirus Any Co-infections Astro/Noro Astro/Adeno Noro/Adeno Note: The sensitivity analysis was not performed because no records were observed for co-infection. Note: Number of SGE hosp. and RV / RV co-infection SGE are computed from the cases in the ATP enrolled cohort with a PCR positive result and from the cases in the ATP with a PCR positive result and possible co-infection, respectively. Secondary outcome: Distribution of cases by year and month of hospitalisations (ATP confirmed cohort) Total N = 215 Characteristics Categories n % Year and month of hospitalisation LL UL

6 N = number of screening cases n = number of screening cases in a given category % = n / Number of screening cases with available results x 100 Secondary outcome: Distribution of RV genotypes for confirmed cases overall and by age group (ATP confirmed cohort) 3-5 N = N = N = N = 21 Categories n % LL UL n % LL UL n % LL UL n % LL UL G-other P[14] G12P[6] G12P[8] G1P[8] G2P[4] G3P[8] G4P[8] G9P[8] MIMI MIP[8] Total N = 215 Categories n % LL UL G-other P[14] G12P[6] G12P[8] G1P[8] G2P[4] G3P[8] G4P[8] G9P[8] MIMI MIP[8] = Between 3 and 6 months of age (6 not included) 6-11 = Between 6 and 12 months of age (12 not included) = Between 12 and 24 months of age (24 not included) 24+ = More than 24 months of age (24 included) N = number of confirmed RV cases n = number of confirmed RV cases with the specified genotype % = n / Number of confirmed RV cases with available results x 100 LL, UL for percentage = Exact 95% Lower and Upper confidence limits MI=mixed infection Conclusion: Vaccine effectiveness of HRV full series (2 doses) in preventing community-acquired RV SGE among hospitalised children born after 1 October 2006 and at least 14 weeks of age was estimated at 90.24%. Date updated: 05-August-2013