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: 112024 (HPV-052 EXT ) Title: Gynaecological follow-up of a subset of 580299/ study subjects Rationale: The aim of this study was to follow-up of a subset of 580299/ study subjects who were either cervical cytology negative and oncogenic HPV positive or pregnant at their final 580299/ 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
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 1467 615 42.6 40.1 45.2 Negative 1467 828 57.4 54.8 59.9 Missing 1467 24 - - - 24 Months post HPV Positive 869 418 48.5 45.1 51.9 Negative 869 444 51.5 48.1 54.9 Missing 869 7 - - - 36 Months post HPV Positive 495 255 51.9 47.4 56.4 Negative 495 236 48.1 43.6 52.6 Missing 495 4 - - - 48 Months post HPV Positive 258 144 57.4 51.0 63.6 Negative 258 107 42.6 36.4 49.0 Missing 258 7 - - - Overall Positive 2001 820 41.2 19.3 21.9 Negative 2001 1171 58.8 28.0 30.8 Missing 2001 10 - - - 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 1467 1193 81.3 79.2 83.3 ASC-US 1467 154 10.5 9.0 12.2 ASC-H 1467 8 0.5 0.2 1.1 LSIL 1467 100 6.8 5.6 8.2 HSIL 1467 8 0.5 0.2 1.1 AGC 1467 4 0.3 0.1 0.7
24 Months Post HPV Normal 867 662 76.4 73.4 79.1 ASC-US 867 117 13.5 11.3 16.0 ASC-H 867 11 1.3 0.6 2.3 LSIL 867 68 7.8 6.1 9.8 HSIL 867 7 0.8 0.3 1.7 AGC 867 2 0.2 0.0 0.8 36 Months Post HPV Normal 494 390 78.9 75.1 82.5 ASC-US 494 58 11.7 9.0 14.9 ASC-H 494 4 0.8 0.2 2.1 LSIL 494 34 6.9 4.8 9.5 HSIL 494 5 1.0 0.3 2.3 AGC 494 3 0.6 0.1 1.8 48 Months Post HPV Normal 258 206 79.8 74.4 84.6 ASC-US 258 28 10.9 7.3 15.3 ASC-H 258 0 0.0 0.0 1.4 LSIL 258 16 6.2 3.6 9.9 HSIL 258 6 2.3 0.9 5.0 AGC 258 2 0.8 0.1 2.8 Overall Normal 2000 1820 91.0 89.7 92.2 ASC-US 2000 312 15.6 14.0 17.3 ASC-H 2000 21 1.1 0.7 1.6 LSIL 2000 189 9.5 8.2 10.8 HSIL 2000 26 1.3 0.9 1.9 AGC 2000 9 0.5 0.2 0.9 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 2003 572 28.6 26.6 30.6 No 2003 1429 71.4 69.4 73.4 Missing 2003 2 - - - Algorithm respected* Yes 392 371 94.6 91.9 96.7 No 392 21 5.4 3.3 8.1 Colposcopy adequacy* Satisfactory 392 370 95.4 92.8 97.2 Unsatisfactory 392 18 4.6 2.8 7.2 Missing 392 4 - - - Colposcopy referral Yes 2003 385 19.3 17.5 21.0 No 2003 1615 80.8 79.0 82.5 Missing 2003 3 - - - Algorithm respected* Yes 263 254 96.9 94.1 98.7 No 263 8 3.1 1.3 5.9 Missing 263 1 - - -
36 Months Post HPV 48 Months Post HPV Colposcopy adequacy* Satisfactory 263 245 94.6 91.1 97.0 Unsatisfactory 263 14 5.4 3.0 8.9 Missing 263 4 - - - Colposcopy referral Yes 2003 224 11.2 9.9 12.7 No 2003 1776 88.8 87.3 90.1 Missing 2003 3 - - - Algorithm respected* Yes 158 154 97.5 93.6 99.3 No 158 4 2.5 0.7 6.4 Colposcopy adequacy* Satisfactory 158 150 95.5 91.0 98.2 Unsatisfactory 158 7 4.5 1.8 9.0 Missing 158 1 - - - Colposcopy referral Yes 2003 133 6.7 5.6 7.8 No 2003 1867 93.4 92.2 94.4 Missing 2003 3 - - - Algorithm respected* Yes 96 96 100 96.2 100 No 96 0 0.0 0.0 3.8 Colposcopy adequacy* Satisfactory 96 92 96.8 91.0 99.3 Unsatisfactory 96 3 3.2 0.7 9.0 Missing 96 1 - - - Overall Colposcopy referral Yes 2003 765 38.2 36.1 40.4 No 2003 1236 61.8 59.6 63.9 Missing 2003 2 - - - Algorithm respected* Yes 625 600 96.2 94.3 97.5 No 625 24 3.8 2.5 5.7 Missing 625 1 - - - Colposcopy adequacy* Satisfactory 625 595 95.2 93.2 96.7 Unsatisfactory 625 29 4.6 3.1 6.6 Missing 625 2 - - - 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 - 199 76 52.1 43.6 60.4 Only CIN1 Positive 199 41 20.6 15.2 26.9 Negative 199 158 79.4 73.1 84.8 Only CIN2 Positive 199 18 9.0 5.4 13.9 Negative 199 181 91.0 86.1 94.6 Only CIN3 Positive 199 8 4.0 1.8 7.8 Negative 199 191 96.0 92.2 98.2 CIN1 and CIN2 Positive 199 3 1.5 0.3 4.3 Negative 199 196 98.5 95.7 99.7 CIN1 and CIN3 Positive 199 1 0.5 0.0 2.8 Negative 199 198 99.5 97.2 100 CIN2 and CIN3 Positive 199 1 0.5 0.0 2.8
24 Months Post HPV 36 Months Post HPV Negative 199 198 99.5 97.2 100 CIN1 and CIN2 and CIN3 Positive 199 0 0.0 0.0 1.8 Negative 199 199 100 98.2 100 AIS Positive 199 0 0.0 0.0 1.8 Negative 199 199 100 98.2 100 Invasive malignancy Positive 199 0 0.0 0.0 1.8 Negative 199 199 100 98.2 100 Other - 199 85 42.7 35.7 49.9 Negative - 147 38 36.5 27.3 46.6 Only CIN1 Positive 147 47 32.0 24.5 40.2 Negative 147 100 68.0 59.8 75.5 Only CIN2 Positive 147 8 5.4 2.4 10.4 Negative 147 139 94.6 89.6 97.6 Only CIN3 Positive 147 8 5.4 2.4 10.4 Negative 147 139 94.6 89.6 97.6 CIN1 and CIN2 Positive 147 2 1.4 0.2 4.8 Negative 147 145 98.6 95.2 99.8 CIN1 and CIN3 Positive 147 0 0.0 0.0 2.5 Negative 147 147 100 97.5 100 CIN2 and CIN3 Positive 147 1 0.7 0.0 3.7 Negative 147 146 99.3 96.3 100 CIN1 and CIN2 and CIN3 Positive 147 0 0.0 0.0 2.5 Negative 147 147 100 97.5 100 AIS Positive 147 1 0.7 0.0 3.7 Negative 147 146 99.3 96.3 100 Invasive malignancy Positive 147 0 0.0 0.0 2.5 Negative 147 147 100 97.5 100 Other - 147 56 38.1 30.2 46.5 Negative - 88 31 43.7 31.9 56.0 Only CIN1 Positive 88 31 35.2 25.3 46.1 Negative 88 57 64.8 53.9 74.7 Only CIN2 Positive 88 6 6.8 2.5 14.3 Negative 88 82 93.2 85.7 97.5 Only CIN3 Positive 88 3 3.4 0.7 9.6 Negative 88 85 96.6 90.4 99.3 CIN1 and CIN2 Positive 88 0 0.0 0.0 4.1 CIN1 and CIN3 Positive 88 0 0.0 0.0 4.1 CIN2 and CIN3 Positive 88 0 0.0 0.0 4.1 CIN1 and CIN2 and CIN3 Positive 88 0 0.0 0.0 4.1 AIS Positive 88 0 0.0 0.0 4.1 Invasive malignancy Positive 88 0 0.0 0.0 4.1 Other - 88 25 28.4 19.3 39.0
48 Months Post HPV Negative - 54 21 47.7 32.5 63.3 Only CIN1 Positive 54 15 27.8 16.5 41.6 Negative 54 39 72.2 58.4 83.5 Only CIN2 Positive 54 5 9.3 3.1 20.3 Negative 54 49 90.7 79.7 96.9 Only CIN3 Positive 54 2 3.7 0.5 12.7 Negative 54 52 96.3 87.3 99.5 CIN1 and CIN2 Positive 54 1 1.9 0.0 9.9 Negative 54 53 98.1 90.1 100 CIN1 and CIN3 Positive 54 0 0.0 0.0 6.6 CIN2 and CIN3 Positive 54 0 0.0 0.0 6.6 CIN1 and CIN2 and CIN3 Positive 54 0 0.0 0.0 6.6 AIS Positive 54 0 0.0 0.0 6.6 Invasive malignancy Positive 54 0 0.0 0.0 6.6 Other Other 54 11 20.4 10.6 33.5 Overall Negative - 369 114 30.9 26.2 35.9 Only CIN1 Positive 369 111 30.1 25.4 35.0 Negative 369 258 69.9 65.0 74.6 Only CIN2 Positive 369 33 8.9 6.2 12.3 Negative 369 336 91.1 87.7 93.8 Only CIN3 Positive 369 19 5.1 3.1 7.9 Negative 369 350 94.9 92.1 96.9 CIN1 and CIN2 Positive 369 10 2.7 1.3 4.9 Negative 369 359 97.3 95.1 98.7 CIN1 and CIN3 Positive 369 1 0.3 0.0 1.5 Negative 369 368 99.7 98.5 100 CIN2 and CIN3 Positive 369 2 0.5 0.1 1.9 Negative 369 367 99.5 98.1 99.9 CIN1 and CIN2 and CIN3 Positive 369 0 0.0 0.0 1.0 Negative 369 369 100 99.0 100 AIS Positive 369 1 0.3 0.0 1.5 Negative 369 368 99.7 98.5 100 Invasive malignancy Positive 369 0 0.0 0.0 1.0 Negative 369 369 100 99.0 100 Other - 369 153 41.5 36.4 46.7 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.
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 392 33 8.4 5.9 11.6 No 392 359 91.6 88.4 94.1 Loop excision of cervix Yes 32 14 43.8 26.4 62.3 No 32 18 56.3 37.7 73.6 Loop cone of cervix Yes 32 15 46.9 29.1 65.3 No 32 17 53.1 34.7 70.9 Cold knife cone of cervix Yes 32 0 0.0 0.0 10.9 No 32 32 100 89.1 100 Laser excision Yes 32 1 3.1 0.1 16.2 No 32 31 96.9 83.8 99.9 Other - 32 4 12.5 3.5 29.0 Treatment referral Yes 263 19 7.3 4.4 11.1 No 263 243 92.7 88.9 95.6 Missing 263 1 - - - Loop excision of cervix Yes 17 9 52.9 27.8 77.0 No 17 8 47.1 23.0 72.2 Loop cone of cervix Yes 17 4 23.5 6.8 49.9 No 17 13 76.5 50.1 93.2 Cold knife cone of cervix Yes 17 1 5.9 0.1 28.7 No 17 16 94.1 71.3 99.9 Laser excision Yes 17 0 0.0 0.0 19.5 No 17 17 100 80.5 100 Other - 17 4 23.5 6.8 49.9 Treatment referral Yes 158 13 8.2 4.5 13.7 No 158 145 91.8 86.3 95.5 Loop excision of cervix Yes 10 4 40.0 12.2 73.8 No 10 6 60.0 26.2 87.8 Loop cone of cervix Yes 10 4 40.0 12.2 73.8 No 10 6 60.0 26.2 87.8 Cold knife cone of cervix Yes 10 0 0.0 0.0 30.8 No 10 10 100 69.2 100 Laser excision Yes 10 0 0.0 0.0 30.8 No 10 10 100 69.2 100 Other - 10 2 20.0 2.5 55.6 Treatment referral Yes 96 9 9.4 4.4 17.1 No 96 87 90.6 82.9 95.6 Loop excision of cervix Yes 8 1 12.5 0.3 52.7 No 8 7 87.5 47.3 99.7 Loop cone of cervix Yes 8 5 62.5 24.5 91.5 No 8 3 37.5 8.5 75.5 Cold knife cone of cervix Yes 8 0 0.0 0.0 36.9 No 8 8 100 63.1 100 Laser excision Yes 8 1 12.5 0.3 52.7 No 8 7 87.5 47.3 99.7 Other - 8 1 12.5 0.3 52.7 Overall Treatment referral Yes 625 58 9.3 7.1 11.9 No 625 566 90.7 88.1 92.9 Missing 625 1 - - - Loop excision of cervix Yes 53 25 47.2 33.3 61.4 No 53 28 52.8 38.6 66.7 Loop cone of cervix Yes 53 20 37.7 24.8 52.1
No 53 33 62.3 47.9 75.2 Cold knife cone of cervix Yes 53 1 1.9 0.0 10.1 No 53 52 98.1 89.9 100 Laser excision Yes 53 2 3.8 0.5 13.0 No 53 51 96.2 87.0 99.5 Other - 53 8 15.1 6.7 27.6 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