The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. Study No.: 111700 (ROTA-070 PMS) Title: Safety of GlaxoSmithKline (GSK) Biologicals oral live attenuated human rotavirus (HRV) vaccine, Rotarix or Rotarix liquid formulation (oral suspension or prefilled syringe) when administered according to the prescribing information in Korea. Rotarix (HRV): GSK Biologicals oral live attenuated human rotavirus (HRV) vaccine. Rationale: HRV lyophilised formulation and HRV liquid formulation (oral suspension as well as prefilled syringe) have both been registered in Korea. The purpose of this post marketing (PMS) study was to assess the safety of all of the HRV vaccine presentations when administered to infants aged from 6 weeks (first dose) to not more than 24 weeks (second dose). A total of at least 3000 evaluable subjects (approximately 500 per year for a period of 6 consecutive years) are required to be enrolled as per the regulations of the Korean Food and Drugs Administration (KFDA). This CTRS presents results collected during Years 1, 2, 3, 4, 5 (Year 1 & Year 2 data were combined and presented at the Year 2 time point and Year 3 & Year 4 data were combined and presented at the Year 4 time point) along with consolidated surveillance data from Year 1 to Year 6 time points Phase: IV Study Period: 02 September 2008 to 20 January 2010 (data lock point at Year 2) 16 August 2010 to 16 January 2012 (data lock point at Year 4) 09 September 2010 to 19 February 2013 (data lock point at Year 5) Year 1 to Year 6 study period: 02 September 2008 to 03 February 2014 (data lock point at Year 6) Study Design: Open, non-comparative, single group, multi-centre study. Centres: 35 centres in Korea (Year 2 time point) 20 centres in Korea (Year 4 time point) 13 centres in Korea (Year 5 time point). Total 83 centres in Korea (Year 1 Year 6 time points) Indication: Prevention of gastroenteritis (GE) caused by rotavirus (RV) in infants from the age of 6 weeks. Treatment: There was one study group, the. Subjects received 2 oral doses of HRV vaccine. The first dose was administered to infants from the age of 6 weeks. The second dose was given at least 4 weeks after Dose 1, preferably before the age of 16 weeks. The 2 doses had to be given before 24 weeks of age. Objective: To assess the safety of HRV lyophilised formulation or HRV liquid formulation (oral suspension or prefilled syringe) in infants when administered according to the prescribing information in Korea. Primary Outcome/Efficacy Variables: Safety: Analysis at Year 2: Occurrence of solicited adverse events (AEs) during the 8-day (Day 0 Day 7) follow-up after each vaccine dose. Occurrence of unsolicited AEs during the 31-day (Day 0 Day 30) follow-up period after each vaccine dose according to Medical Dictionary for Regulatory Activities (MedDRA) classification. Occurrence of serious adverse events (SAEs) during the entire post-marketing surveillance (PMS) period. Following protocol amendment, the outcome variables for the subsequent study periods were reformulated as below: Analysis at Years 3, 4, 5 & 6*: Occurrence of AEs during the 31-day (Day 0 Day 30) follow-up period after each vaccine dose according to MedDRA classification. Occurrence of SAEs during the entire PMS period. Outcome variables were not differentiated into primary and secondary in the study protocol, hence all were considered as primary outcome variables. *In line with the KFDA s request, the consolidated surveillance data from Year 1 to Year 6 time points were presented in place of Year 6. Secondary Outcome/Efficacy Variable(s): Not applicable. Statistical Methods:
The analysis was performed on the Total Vaccinated cohort, which included all vaccinated subjects with at least one dose of HRV vaccine administration documented. Analysis of Safety The analysis was performed on the Total Vaccinated cohort. For the Year 1 & 2 study period, the incidence of solicited symptoms occurring during the 8-day (Days 0 7) follow-up period after vaccination was tabulated with 95% confidence interval (CI). The same tabulation was performed for Grade 3 symptoms. The percentage of subjects with at least one report of unsolicited AEs during the 31-day (Days 0 30) follow-up period after each vaccine dose was tabulated according to MedDRA preferred terms for the Years 2 and 4 time points, and according to World Health Organisation s Adverse Reactions Terminology (WHO ART) Dictionary for the Year 5 and consolidated results from Year 1 to Year 6 time points. SAEs were collected and summarized according to MedDRA preferred terms up to Year 4 time point, and according to WHO ART Dictionary for the Year 5 and consolidated results from Year 1 to Year 6 time points. Study Population: Male or female subject of at least 6 weeks of age at the time of the first vaccination. Written informed consent was obtained from parents or guardians of the subjects prior to study entry. Number of subjects (Year 2 time point) Planned, N* 1000 Randomized, N (Total Vaccinated cohort) 876 Completed n (%) 699 (79.8) Total Number Subjects Withdrawn, n (%) 177 (20.2) Withdrawn due to Adverse Events, n (%) 1 (0.1) Withdrawn for other reasons, n (%) 176 (20.1) N (Total Vaccinated cohort) 876 Females: Males 436:440 Mean Age, weeks (SD) 9.6 (2.35) Korean, n (%) 874 (99.8) Number of subjects (Year 4 time point) Planned, N* 1000 Randomized, N (Total Vaccinated cohort) 1052 Completed, n (%) 892 (84.8) Total Number Subjects Withdrawn, n (%) 160 (15.2) Withdrawn due to Adverse Events, n (%) 2 (0.2) Withdrawn for other reasons, n (%) 158 (15.0) N (Total Vaccinated cohort) 1052 Females: Males 539:513 Mean Age, weeks (SD) 9.6 (2.30) Korean, n (%) 1050 (99.8) Number of subjects (Year 5 time point) Planned, N* 500 Randomized, N (Total Vaccinated cohort) 708 Completed, n (%) 579 (81.8) Total Number Subjects Withdrawn, n (%) 129 (18.2) Withdrawn due to Adverse Events, n (%) 1 (0.1) Withdrawn for other reasons, n (%) 128 (18.1) N (Total Vaccinated cohort) 708 Females: Males 309:399 Mean Age, weeks (SD) 9.5 (2.06) Korean, n (%) 708 (100) Number of subjects (Year 1-6 time point)
Planned, N* 3000 Randomized, N (Total Vaccinated cohort) 3111 Completed, n (%) 2569 (82.6) Total Number Subjects Withdrawn, n (%) 542 (17.4) Withdrawn due to Adverse Events, n (%) 5 (0.16) Withdrawn for other reasons, n (%) 537 (17.3) N (Total Vaccinated cohort) 3111 Females: Males 1525:1586 Mean Age, weeks (SD) 9.6 (2.22) Korean, n (%) 3107 (99.9) *It was planned to enroll 500 subjects each year. Primary Efficacy Results: Occurrence of unsolicited AEs and SAEs, please refer to the safety section of the CTRS. Primary Efficacy Results: Number (%) of subjects with solicited general symptom during the 8-day (Day 0 Day 7) postvaccination period following each dose and across doses in the Year 1 & 2 study period (Total Vaccinated cohort). Symptom Intensity N n % 95 % CI LL UL Dose 1 Cough Any 810 150 18.5 15.9 21.4 Grade 3 810 1 0.1 0.0 0.7 Diarrhoea Any 810 36 4.4 3.1 6.1 Grade 3 810 3 0.4 0.1 1.1 Irritability Any 810 349 43.1 39.6 46.6 Grade 3 810 26 3.2 2.1 4.7 Loss of appetite Any 810 208 25.7 22.7 28.8 Grade 3 810 3 0.4 0.1 1.1 Temperature (Axillary) 37.5 C 810 114 14.1 11.8 16.7 >39.0 C 810 3 0.4 0.1 1.1 Vomiting Any 810 166 20.5 17.8 23.4 Grade 3 810 40 4.9 3.6 6.7 Dose 2 Cough Any 699 86 12.3 10.0 15.0 Grade 3 699 1 0.1 0.0 0.8 Diarrhoea Any 699 15 2.1 1.2 3.5 Grade 3 699 2 0.3 0.0 1.0 Irritability Any 699 139 19.9 17.0 23.0 Grade 3 699 5 0.7 0.2 1.7 Loss of appetite Any 699 88 12.6 10.2 15.3 Grade 3 699 1 0.1 0.0 0.8 Temperature (Axillary) 37.5 C 699 33 4.7 3.3 6.6 >39.0 C 699 0 0.0 0.0 0.5 Vomiting Any 699 58 8.3 6.4 10.6 Grade 3 699 16 2.3 1.3 3.7 Across Doses Cough Any 876 204 23.3 20.5 26.2 Grade 3 876 2 0.2 0.0 0.8 Diarrhoea Any 876 50 5.7 4.3 7.5 Grade 3 876 5 0.6 0.2 1.3 Irritability Any 876 405 46.2 42.9 49.6 Grade 3 876 31 3.5 2.4 5.0 Loss of appetite Any 876 259 29.6 26.6 32.7 Grade 3 876 4 0.5 0.1 1.2 Temperature (Axillary) 37.5 C 876 135 15.4 13.1 18.0 >39.0 C 876 3 0.3 0.1 1.0
Vomiting Any 876 200 22.8 20.1 25.8 Grade 3 876 53 6.1 4.6 7.8 N = number of subjects with at least one administered dose n (%) = number (percentage) of subjects reporting at least once the symptom 95% CI = Exact 95% confidence interval; LL = lower limit, UL = upper limit Any = occurrence of the specified general symptom regardless of intensity grade Grade 3 Cough = Cough/runny nose which prevented daily activity Grade 3 Diarrhoea = 6 looser than normal stools/day Grade 3 Irritability = Crying that could not be comforted/prevented normal activity Grade 3 Loss of appetite = Did not eat at all Grade 3 Vomiting = 3 episodes of vomiting/day Secondary Outcome Variable(s): Not applicable. Safety Results: Number (%) of subjects with unsolicited AEs* during the 31-day (Day 0 Day 30) follow-up period after each vaccine dose Year 1 & 2 study period (Total Vaccinated cohort) Most frequent AEs - On-Therapy (occurring within Day 0 Day 30 following vaccination) N = 876 Subjects with any AE(s), n (%) 334 (38.1) Upper respiratory tract infection 80 (9.1) Nasopharyngitis 79 (9.0) Bronchiolitis 64 (7.3) Dermatitis atopic 34 (3.9) Gastrointestinal disorder 26 (3.0) Gastroenteritis 24 (2.7) Bronchitis 12 (1.4) Dermatitis 12 (1.4) Pharyngitis 10 (1.1) Gastritis 8 (0.9) Rhinitis 8 (0.9) *Unsolicited AEs were classified according to MedDRA preferred term Safety Results: Number (%) of subjects with unsolicited AEs* during the 31-day (Day 0 Day 30) follow-up period after each vaccine dose Year 3 & 4 study period (Total Vaccinated cohort) Most frequent adverse events On-Therapy (occurring within Day 0 Day 30 following vaccination) N = 1052 Subjects with any AE(s), n (%) 413 (39.3) Upper respiratory tract infection 117 (11.1) Pyrexia 74 (7.0) Diarrhoea 48 (4.6) Bronchiolitis 39 (3.7) Bronchitis 36 (3.4) Gastroenteritis 30 (2.9) Vomiting 28 (2.7) Dyspepsia 23 (2.2) Rash 23 (2.2) Rhinorrhoea 18 (1.7) *Unsolicited AEs were classified according to MedDRA preferred term Safety Results: Number (%) of subjects with unsolicited AEs* during the 31-day (Day 0 Day 30) follow-up period after each vaccine dose Year 5 study period (Total Vaccinated cohort) Most frequent adverse events On-Therapy (occurring within Day 0 Day 30 following vaccination) N = 708 Subjects with any AE(s), n (%) 254 (35.9) Bronchiolitis 42 (5.9) Common cold 41 (5.8)
Fever 34 (4.8) Coughing 24 (3.4) Rhinorrhoea 18 (2.5) Bronchitis 17 (2.4) Diarrhoea 17 (2.4) Rash 17 (2.4) Upper respiratory tract infection 17 (2.4) Otitis media 14 (2.0) *Unsolicited AEs were classified according to WHO ART Dictionary terms. Safety Results: Number (%) of subjects with unsolicited AEs* during the 31-day (Day 0 Day 30) follow-up period after each vaccine dose Year 1 to Year 6 study period (Total Vaccinated cohort) Most frequent AEs - On-Therapy (occurring within Day 0 Day 30 following vaccination) N = 3111 Subjects with any AE(s), n (%) 1201 (38.6) Upper respiratory tract infection 269 (8.6) Bronchiolitis 159 (5.1) Fever 138 (4.4) Common cold 129 (4.1) Gastroenteritis 109 (3.5) Bronchitis 93 (3.0) Diarrhoea 70 (2.3) Dermatitis atopic 64 (2.1) Otitis media 60 (1.9) Rash 51 (1.6) *Unsolicited AEs were classified according to WHO ART Dictionary terms Safety Results: Number (%) of subjects with SAEs* Year 1 & 2 study period (Total Vaccinated cohort) N = 876 Subjects with any SAE(s), n (%) [n assessed by the investigator as related] 6 (0.7) [0] Bronchiolitis 4 (0.5) [0] Gastroenteritis 2 (0.2) [0] Otitis media acute 2 (0.2) [0] Croup infectious 1 (0.1) [0] Ileus paralytic 1 (0.1) [0] Sepsis 1 (0.1) [0] N = 876 *SAEs were classified according to MedDRA preferred term Safety Results: Number (%) of subjects with SAEs* Year 3 & 4 study period (Total Vaccinated cohort) N = 1052 Subjects with any SAE(s), n (%) [n assessed by the investigator as related] 13 (1.2) [0] Bronchiolitis 3 (0.3) [0] Urinary tract infection 3 (0.3) [0] Pneumonia 2 (0.2) [0] Bronchitis 1 (0.1) [0] Cytomegalovirus infection 1 (0.1) [0] Gastroenteritis 1 (0.1) [0] Gastroenteritis rotavirus 1 (0.1) [0]
Hydronephrosis 1 (0.1) [0] Otitis media acute 1 (0.1) [0] Pneumonia respiratory syncytial viral 1 (0.1) [0] Pyrexia 1 (0.1) [0] Upper respiratory tract infection 1 (0.1) [0] N = 1052 *SAEs were classified according to MedDRA preferred term Safety Results: Number (%) of subjects with SAEs* Year 5 study period (Total Vaccinated cohort) N = 708 Subjects with any SAE(s), n (%) [n assessed by the investigator as related] 4 (0.6) [0] Bronchiolitis 1 (0.1) [0] Bronchopneumonia 1 (0.1) [0] Colitis 1 (0.1) [0] Otitis Media 1 (0.1) [0] Pneumonia 1 (0.1) [0] N = 708 *SAEs were classified according to WHO ART Dictionary terms. Safety Results: Number (%) of subjects with SAEs* Year 1 to Year 6 study period (Total Vaccinated cohort) N = 3111 Subjects with any SAE(s), n (%) [n assessed by the investigator as related] 26 (0.8) [0] Bronchiolitis 9 (0.3) [0] Otitis Media 4 (0.1) [0] Pneumonia 4 (0.1) [0] Gastroenteritis 3 (0.1) [0] Urinary Tract Infection 3 (0.1) [0] Bronchitis 2 (0.1) [0] Bronchopneumonia 1 (0.0) [0] Colitis 1 (0.0) [0] Croup 1 (0.0) [0] Cytomegalovirus Gastrointestinal Infection 1 (0.0) [0] Fever 1 (0.0) [0] Gastroenteritis Viral 1 (0.0) [0] Hydronephrosis 1 (0.0) [0] Ileus Paralytic 1 (0.0) [0] Pneumonia Viral 1 (0.0) [0] Sepsis 1 (0.0) [0] Upper Respiratory Tract Infection 1 (0.0) [0] N = 3111 *SAEs were classified according to WHO ART Dictionary terms Conclusion: During the Year 1 and 2 study period, irritability and loss of appetite were the most frequently reported solicited general symptoms across doses (46.2% and 29.6% of the subjects, respectively) in the 8-day solicited follow-up period following each vaccination. At least one unsolicited AE was reported for 334 (38.1%) subjects during the Year 1 & 2 study period, for 413 (39.3%) subjects during the Year 3 & 4 study period, for 254 (35.9%) subjects during the Year 5 study period and for 1201 (38.6%)
subjects during the Year 1 to Year 6 study period. At least one SAE was reported for 6 (0.7%) subjects during the Year 1 & 2 study period, for 13 (1.2%) subjects during the Year 3 & 4 study period, for 4 (0.6%) subjects during the Year 5 study period and for 26 (0.8%) subjects during the Year 1 to Year 6 study period. All of the SAEs reported up to Year 6 were assessed by the investigators as not related to the vaccination; no fatal SAEs were reported up to Year 6. Date updated: 21-October-2014