Study Number: Title: Rationale: Phase: Study Period Study Design: Centres: Indication Treatment: Objectives: Primary Outcome/Efficacy Variable:

Transcription

1 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 Number: (HPV-052 EXT ) Title: Gynaecological follow-up of a subset of / study subjects Rationale: The aim of this study was to follow-up of a subset of / study subjects who were either cervical cytology negative and oncogenic HPV positive or pregnant at their final / study visit (Visit 10 at Month 48) Phase: IIIb Study Period: From 05 Aug 2009 to 20 Jan 2014 Study Design: Open study on one group, multi-centre Centres: 85 centres: 5 in Australia, 3 in Belgium, 3 in Brazil, 5 in Canada, 15 in Finland, 14 in Germany, one in Italy, 7 in Philippines, 5 in Spain, 3 in Taiwan, 3 in Thailand, 3 in United Kingdom, 18 in United States. Indication: The human papillomaviruses (HPV)-16/18 vaccine is indicated in females from 9 years of age onwards for the prevention of persistent infection, premalignant genital (cervical, vulvar and vaginal) lesions and cervical, vulvar and vaginal cancers (squamous-cell carcinoma and adenocarcinoma) caused by oncogenic HPV types. Treatment: No vaccine was administered during this study. The study group consisted a subset of HPV- subjects who at their last study visit of study HPV- (Visit 10, Month 48) displayed normal cervical cytology but tested positive for oncogenic HPV infection or were pregnant so that no cervical sample could be collected at that visit. Objectives: To provide clinical management and, if required, treatment to subjects who at the end of the HPV- study displayed normal cervical cytology but tested positive for oncogenic HPV infection or to subjects who were pregnant at the end of the HPV- study so that no cervical sample could be collected. To report fatal serious adverse events (SAEs), SAEs related to study participation and SAEs related to a concurrent GSK medication in all subjects. Primary Outcome/Efficacy Variable: Evaluation of the presence of oncogenic HPV DNA in cervical samples by HPV DNA testing (Hybrid Capture 2 test [HCII]). Evaluation of cervical cytological abnormalities in cervical samples by ThinPrep PapTest. Occurrence of referral to colposcopy. Evaluation of colposcopy outcomes and biopsy results according to local laboratories. Occurrence of referrals to treatment. Evaluation of local cervical therapy performed and treatment biopsy results according to local laboratories. Occurrence of fatal SAEs. Occurrence and intensity of SAEs assessed as possibly related to study participation. Occurrence and intensity of SAEs assessed as possibly related to a concurrent GSK medication. Withdrawals from the study due to AEs or SAEs. Secondary Outcome/Efficacy Variable(s): Outcome variables were not differentiated into primary and secondary in the study protocol; all are considered as primary outcome variables for this study. Statistical Methods: The analysis was performed on the Total HPV-052 cohort includes the HPV- subjects who at their last HPV- study visit at Month 48 displayed normal cervical cytology but tested positive for oncogenic HPV infection or who were pregnant so that no cervical sample could be collected at that visit and who attended any visit in this study. Analysis of Safety The analysis of safety was performed on the total HPV-052 cohort The percentage of subjects with oncogenic HPV DNA in cervical samples by HCII, colposcopy referral and adequacy, cervical cytology and biopsy result, treatment referrals and treatment type and their 95% confidence intervals were tabulated at each timepoint. The percentage of subjects with SAEs and SAEs that are possibly related to study participation, a concurrent GSK medication and percentage of subjects with AEs or SAEs leading to withdrawal were tabulated. Study Population: Subset of HPV- study subjects (15-25 years old at first study vaccination), who at their last study visit of HPV- (Visit 10, Month 48) displayed normal cervical cytology but tested positive for oncogenic HPV infection, or were pregnant and hence no cervical sample could be collected at that visit. Written informed consent

2 was obtained from the subjects prior to enrolment. Number of Subjects: Planned, N 2000 Entered, N (Total HPV-052 cohort) 2003 Completed, n (%) 1787 (89.2) Total Number Subjects Withdrawn, n (%) 216 (10.8) Withdrawn due to Adverse Events, n (%) 0 (0.0) Withdrawn due to Lack of Efficacy, n (%) Not Applicable Withdrawn for other reasons, n (%) 216 (10.8) Demographics N (Total HPV-052 cohort) 2003 Sex, n (%) Females 2003 (100) Mean Age, years (SD) 24.3 (3.06) Median Age, years 23.0 Minimum, Maximum (19,32) White/Caucasian, n (%) 1211 (60.5) East & South East Asian, n (%) 549 (27.4) Chinese, n (%) 106 (5.3) Primary Outcome Results: Number (%) of subject with their HPV DNA status by HCII at each yearly study visit (Total HPV-052 cohort) Study Month HPV DNA result N n % LL UL 12 Months post HPV Positive Negative Missing Months post HPV Positive Negative Missing Months post HPV Positive Negative Missing Months post HPV Positive Negative Missing Overall Positive Negative Missing N = number of subjects n = number of subjects in a given category % = n / Number of subjects with available results x 100 LL, UL = Exact 95% Lower and Upper confidence limits Missing = For some of the subjects whose result is QNS Primary Outcome Results: Number (%) of subjects with cervical cytology result at each yearly study visit (Total HPV- 052 cohort) Study Month Cervical cytology result N n % LL UL 12 Months Post HPV Normal ASC-US ASC-H LSIL HSIL AGC

3 24 Months Post HPV Normal ASC-US ASC-H LSIL HSIL AGC Months Post HPV Normal ASC-US ASC-H LSIL HSIL AGC Months Post HPV Normal ASC-US ASC-H LSIL HSIL AGC Overall Normal ASC-US ASC-H LSIL HSIL AGC N = number of subject number n = number of subject number in a given category % = n / Number of subject number with available results x 100 LL, UL = Exact 95% Lower and Upper confidence limits ASC-US = Atypical Squamous Cell of Undetermined Significance LSIL = Low-grade Squamous Intraepithelial Lesions HSIL= High-grade Squamous Intraepithelial Lesions AGC = Atypical Glandular Cells ASC-H = Atypical Squamous Cells cannot exclude HSIL Primary Outcome Results: Number (%) of subjects with colposcopy referral and colposcopy adequacy at each study visit (Total HPV-052 cohort) Study Month Characteristics Categories N n % LL UL 12 Months Post HPV 24 Months Post HPV Colposcopy referral Yes No Missing Algorithm respected* Yes No Colposcopy adequacy* Satisfactory Unsatisfactory Missing Colposcopy referral Yes No Missing Algorithm respected* Yes No Missing

4 36 Months Post HPV 48 Months Post HPV Colposcopy adequacy* Satisfactory Unsatisfactory Missing Colposcopy referral Yes No Missing Algorithm respected* Yes No Colposcopy adequacy* Satisfactory Unsatisfactory Missing Colposcopy referral Yes No Missing Algorithm respected* Yes No Colposcopy adequacy* Satisfactory Unsatisfactory Missing Overall Colposcopy referral Yes No Missing Algorithm respected* Yes No Missing Colposcopy adequacy* Satisfactory Unsatisfactory Missing N = number of subjects n = number of subjects in a given category % = n / Number of subjects with available result x 100 LL, UL = Exact 95% Lower and Upper confidence limits * = number of subjects for whom colposcopy has been performed Primary Outcome Results: Number (%) of cervical biopsy results at each study visit (Total HPV-052 cohort) Study Month Cervical biopsy result Categories N n % LL UL 12 Months Post HPV Negative Only CIN1 Positive Negative Only CIN2 Positive Negative Only CIN3 Positive Negative CIN1 and CIN2 Positive Negative CIN1 and CIN3 Positive Negative CIN2 and CIN3 Positive

5 24 Months Post HPV 36 Months Post HPV Negative CIN1 and CIN2 and CIN3 Positive Negative AIS Positive Negative Invasive malignancy Positive Negative Other Negative Only CIN1 Positive Negative Only CIN2 Positive Negative Only CIN3 Positive Negative CIN1 and CIN2 Positive Negative CIN1 and CIN3 Positive Negative CIN2 and CIN3 Positive Negative CIN1 and CIN2 and CIN3 Positive Negative AIS Positive Negative Invasive malignancy Positive Negative Other Negative Only CIN1 Positive Negative Only CIN2 Positive Negative Only CIN3 Positive Negative CIN1 and CIN2 Positive CIN1 and CIN3 Positive CIN2 and CIN3 Positive CIN1 and CIN2 and CIN3 Positive AIS Positive Invasive malignancy Positive Other

6 48 Months Post HPV Negative Only CIN1 Positive Negative Only CIN2 Positive Negative Only CIN3 Positive Negative CIN1 and CIN2 Positive Negative CIN1 and CIN3 Positive CIN2 and CIN3 Positive CIN1 and CIN2 and CIN3 Positive AIS Positive Invasive malignancy Positive Other Other Overall Negative Only CIN1 Positive Negative Only CIN2 Positive Negative Only CIN3 Positive Negative CIN1 and CIN2 Positive Negative CIN1 and CIN3 Positive Negative CIN2 and CIN3 Positive Negative CIN1 and CIN2 and CIN3 Positive Negative AIS Positive Negative Invasive malignancy Positive Negative Other N = number of subjects for whom cervical biopsy results is available at each visit n = number of subjects in a given category % = n / Number of subjects with available results x 100 CIN1 = Cervical Intraepithelial Neoplasia grade 1 CIN2 = Cervical Intraepithelial Neoplasia grade 2 CIN3 = Cervical Intraepithelial Neoplasia grade 3 AIS = Adenocarcinoma in situ Note: Only CIN1/Only CIN2/Only CIN3 categories contain the subject who has only CIN1/CIN2/CIN3 but not the combinations.

7 Primary Outcome Results: Number (%) of subjects with treatment referrals and treatment type according to local medical practice (Total HPV-052 cohort) Study Month Characteristics Categories N n % LL UL 12 Months Post HPV 24 Months Post HPV 36 Months Post HPV 48 Months Post HPV Treatment referral Yes No Loop excision of cervix Yes No Loop cone of cervix Yes No Cold knife cone of cervix Yes No Laser excision Yes No Other Treatment referral Yes No Missing Loop excision of cervix Yes No Loop cone of cervix Yes No Cold knife cone of cervix Yes No Laser excision Yes No Other Treatment referral Yes No Loop excision of cervix Yes No Loop cone of cervix Yes No Cold knife cone of cervix Yes No Laser excision Yes No Other Treatment referral Yes No Loop excision of cervix Yes No Loop cone of cervix Yes No Cold knife cone of cervix Yes No Laser excision Yes No Other Overall Treatment referral Yes No Missing Loop excision of cervix Yes No Loop cone of cervix Yes

8 No Cold knife cone of cervix Yes No Laser excision Yes No Other N = number of subjects n = number of subjects in a given category % = n / Number of subjects with available results x 100 LL, UL = Exact 95% Lower and Upper confidence limits Primary Outcome Results: Number of subjects with AEs or SAEs leading to withdrawal throughout the study (Total HPV-052 cohort) HPV-052 Study Group N = 2003 Number of subjects withdrawn, n (%) 216 (10.8) Reasons for withdrawal, n (%) Serious Adverse Event 0 (0.0) Non-Serious Adverse Event 0 (0.0) Safety Results: Number (%) of subjects with any fatal SAE, study participation or GSK concomitant medication (Total HPV-052 cohort) Serious Adverse Events, n (%) [n considered by the investigator to be related to study medication] All SAEs HPV-052 Study Group N = 2003 Subjects with any SAEs, n (%) [n assessed by the investigator as related] 0 (0.0) [0] HPV-052 Study Group N = 2003 Subjects with fatal SAEs, n (%) [n assessed by the investigator as related] 0 (0.0) [0] Conclusion: This study provided clinical management and treatment when required to the subjects who at the end of the HPV- study displayed normal cervical cytology but tested positive for oncogenic HPV infections or to subjects who were pregnant at the end of the HPV- study so no cervical sample could be collected. Throughout the 4-year follow-up, 820 subjects [41.2%, : 19.3%, 21.9%] tested as HPV-DNA positive by HCII in at least one of their cytology samples. The majority of the subjects [91.0%, : 89.7%, 92.2%] had normal cytology. Seven hundred and sixty five [38.2%, : 36.1%, 40.4%] subjects were referred to a colposcopy examination, and 58 subjects [9.3%, : 7.1%, 11.9%] were referred for a treatment, according to local medical practice. There were no SAEs with fatal outcome or related to the study participation or related to the concomitant GSK medications reported during the study period. No subjects withdrew from study due to an AE or SAE. Date updated: 13-September-2017