The study listed may iclude approved ad o-approved uses, formulatios or treatmet regimes. The results reported i ay sigle study may ot reflect the overall results obtaied o studies of a product. Before prescribig ay product metioed i this Register, healthcare professioals should cosult prescribig iformatio for the product approved i their coutry. GSK Medicie: Cervarix, Huma Papillomavirus vaccie (Types 16, 18) Study Number: 116239 (EPI-HPV-040 VS UK) Title: A observatioal cohort study to assess the risk of autoimmue i adolescet ad youg adult wome aged 9 to 25 years exposed to Cervarix i the Uited Kigdom. Cervarix (HPV): GlaxoSmithKlie (GSK) Biologicals huma papillomavirus (HPV) vaccie Ratioale: The aim of this study was to assess the risk of autoimmue disease(s) withi 12 moths of receivig the first dose of HPV vaccie i the exposed cohort ad over a comparable period i the uexposed cohorts. This study was proposed for addressig the US FDA commitmet. This was a Targeted Safety Study ad a o-imposed Post Authorisatio Safety Study. Study Period: From 30 Aug 2012 to 17 March 2015 (database study). Objectives: Primary To assess the risk of euroiflammatory/ophthalmic autoimmue (ADs) ad other pre-specified ADs withi 12 moths followig the admiistratio of the first dose of HPV vaccie Secodary To describe idividually the icidece of the pre-specified ADs cosiderig differet time periods followig the admiistratio of the first dose of HPV vaccie Icidece of Guillai Barre Sydrome (GBS) (icludig Miller Fisher sydrome ad other variats), ad AI haemolytic aaemia withi two moths followig the admiistratio of the first dose of HPV vaccie Icidece of ITP withi six moths followig the admiistratio of the first dose of HPV vaccie Icidece of multiple sclerosis, trasverse myelitis, optic euritis, other demyeliatig, autoimmue uveitis, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), juveile rheumatoid arthritis (JRA), Still s disease, psoriatic arthritis, akylosig spodylitis, type 1 diabetes mellitus, autoimmue (AI) thyroiditis (icludig Hashimoto s disease, Grave s/basedow disease) ad iflammatory bowel / hepatic disease (Croh s disease, ulcerative colitis ad AI hepatitis) withi oe year followig the admiistratio of the first dose of HPV vaccie Idicatio: The HPV vaccie is idicated for the prevetio of cervical cacer by protectig agaist icidet ad persistet ifectios, cytological abormalities icludig atypical squamous cells of udetermied sigificace (ASC-US), cervical itraepithelial eoplasia (CIN) ad pre-cacerous lesios (CIN 2/3) caused by ocogeic huma papillomaviruses (HPV). Study Ivestigators/Ceters: This was a database study coducted i the Uited Kigdom (UK). Research Methods: The Cliical Practice Research Datalik Geeral Practitioer OLie database (CPRD GOLD) is oe of the largest computerised databases of liked aoymised logitudial medical records from primary care. CPRD GOLD cotais coded records from UK geeral practices ad its liked compoet of the Hospital Episodes Statistics (HES). Data Source: The data sources were CPRD GOLD icludig free text etries ad HES. Algorithms were used to idetify subjects with CPRD GOLD medcodes that correspods to the selected ADs. After first patiet profile review, idividual data with doubt o the aetiology were reviewed by a expert pael. Study Desig: This was a observatioal cohort study with 4 cohorts (1 exposed female cohort ad 3 uexposed cohorts). A self-cotrolled case-series (SCCS) aalysis for cofirmed AD i the exposed female cohort was also coducted. Study Populatio: Male ad female subjects as follows: Female populatio was composed of female subjects vacciated with HPV vaccie betwee the ages of 9 to 25 years ad uexposed female subjects of the same age, idetified from historical data. Female subjects icluded i the exposed cohort had received at least oe dose of HPV vaccie admiistered accordig to local practice. Male populatio was composed of 9- to 25-year-old male subjects ot vacciated with HPV vaccie. Study Exposures, Outcomes: Four cohorts were defied based o exposure to HPV vaccie ad sex as recorded i the CPRD GOLD data source: Exposed Female cohort: icluded wome aged betwee 9 ad 25 years at referece date ad with at least oe dose of HPV vaccie betwee 1 st September 2008 ad 31 st August 2010. The referece date was the date of the first HPV vacciatio Uexposed Female cohort (No-exposed Historical Female cohort): icluded wome aged betwee 9 to 25 years at referece date. The subjects were frequecy matched for age ad practice regio idetifier to the subjects icluded i the vacciated (exposed) cohort. The referece date for the historical female cohort was betwee 1 st
September 2005 ad 31 st August 2007. Cocurret Male cohort (No-exposed Cocurret Male cohort): Male populatio was composed of 9- to 25-year-old male subjects ot vacciated with HPV vaccie. The referece date for the cocurret male cohort was betwee 1 st September 2008 ad 31 st August 2010. Historical Male cohort (No-exposed Historical Male cohort): Male populatio was composed of 9- to 25-year-old male subjects ot vacciated with HPV vaccie. The referece date for the historical male cohort was betwee 1 st September 2005 ad 31 st August 2007. Compariso of the uexposed cocurret male cohort with the uexposed historical male cohort was used as a iteral cotrol for chages over time i CPRD GOLD i reportig ADs. The male subjects were frequecy matched for age ad practice regio idetifier to the subjects icluded i the vacciated (exposed) cohort. The referece date of the uexposed cohorts was a radom date selected amog the referece dates of the matched exposed cohort (mius 3 years for the historical cohorts). Primary edpoit: Occurrece of ew oset of cofirmed $ ADs durig the period of oe year followig admiistratio of at least the first dose of HPV vaccie amog a exposed cohort ad durig a equivalet time period i the o-exposed cohorts for the followig two co-primary composite edpoits: Neuroiflammatory/ophthalmic ADs: Multiple Sclerosis, Trasverse myelitis, Optic euritis, Guillai-Barré sydrome (GBS), icludig Miller Fisher sydrome ad other variats Other demyeliatig : Acute dissemiated ecephalomyelitis, icludig site specific variats: e.g. oifectious ecephalitis, ecephalomyelitis, myelitis, myeloradiculomyelitis, AI peripheral europathies ad plexopathies (icludig chroic iflammatory demyeliatig polyeuropathy, multifocal motor europathy ad polyeuropathies associated with moocloal gammopathy). AI uveitis Other ADs: SLE AD with rheumatologic coditios: RA, JRA, Still s disease, Psoriatic arthritis, Akylosig Spodylitis AI haematological coditios: ITP, AI haemolytic aaemia AI edocrie coditios: Type 1 diabetes mellitus, AI thyroiditis icludig Hashimoto s disease, Grave s/basedow disease. Iflammatory bowel /Hepatic : Croh s, Ulcerative colitis, autoimmue hepatitis. $ Autoimmue disease diagosis ascertaimet by a expert physicia pael Secodary edpoit: Secodary outcome was the occurrece of ew of idividual cofirmed ADs durig the followig specific periods: Occurrece of GBS (icludig Miller Fisher sydrome ad other variats), ad AI haemolytic aaemia withi two moths followig the admiistratio of the first dose of HPV vaccie; Occurrece of ITP withi six moths followig the admiistratio of the first dose of HPV vaccie; Occurrece of multiple sclerosis, trasverse myelitis, optic euritis, other demyeliatig (Acute dissemiated ecephalomyelitis, icludig site specific variats: e.g. o-ifectious ecephalitis, ecephalomyelitis, myelitis, myeloradiculomyelitis, AI peripheral europathies ad plexopathies icludig chroic iflammatory demyeliatig polyeuropathy, multifocal motor europathy ad polyeuropathies associated with moocloalgammopathy). AI uveitis, SLE, RA, JRA, Still s disease, psoriatic arthritis, akylosig spodylitis, type 1 diabetes mellitus, AI thyroiditis (icludig Hashimoto s disease, Grave s/basedow disease), ad iflammatory bowel / hepatic disease (Croh s disease, ulcerative colitis ad AI hepatitis) withi oe year followig the admiistratio of the first dose of HPV vaccie. Data Aalysis Methods: The Total cohort icluded all the four cohorts described above [HPV vaccie exposed female Cohort, No-exposed female Cohort (No-exposed historical female Cohort): Cocurret male Cohort (No-exposed cocurret male cohort), Historical male Cohort (No-exposed Historical male cohort)]. Demographic ad baselie characteristics of the overall study populatio (age at referece date, Geographical distributio, availability of data i CPRD GOLD [follow-up time withi CPRD GOLD at referece date, proportio of Hospital Episode Statistics (HES) likage] ad healthcare resources utilizatio, the year prior to the referece date) were summarized ad tabulated per cohort ad overall, usig descriptive statistics: of subjects, mea, stadard deviatio (SD), media, miimum ad maximum; or (, %). Exposure to live atteuated vaccies or other vaccies or ovel adjuvated vaccies was summarised ad tabulated
i frequecy tables (, %) per cohort ad period (the year prior the referece date ad durig the follow-up period). Frequecy of idividual ADs durig the oe year follow-up period followig the admiistratio of first dose of HPV vaccie by exposed/o-exposed status were summarized ad tabulated. The compariso of the icidece rates of autoimmue was doe usig a Poisso regressio model ageadjusted. The aalysis was also performed for the two male cohorts (cocurret ad historical cohorts). The iferetial statistics for idividual were performed if at least 10 were observed i both female cohorts. A SCCS aalysis for both co-primary edpoits ad idividual was performed for the exposed female cohort. Limitatios: Not applicable Study Results Demographic Characteristics (for overall study populatio) Exposed Female Cohort (N=64964) No- Exposed Female Cohort (N=64973) Cocurret Male Cohort N=(64974) Historical Male Cohort (N=64965) Total (N=259876) Age at referece date Mea (SD) 15.33 (2.09) 15.42 (2.10) 15.27 (2.09) 16 (2.01) 15.51 (2.10) Age at referece date [by age classes] Geographical distributio HES lik Number of years of follow-up i CPRD GOLD at referece date Number of Healthcare resources utilizatio $ (i quartile) the year prior to referece date 9-17 years 58736 (90.4%) 18-25 years North Eglad 6228 (9.5%) 36818 (56.7%) 58655 (90.2%) 6318 (9.7%) 34646 (53.3%) 59242 (91.2%) 5732 (8.8%) 35906 (55.3%) 56232 (86.6%) 232865 (89.6%) 8733 (13.5%) 27011 (10.3%) 33247 (51.2%) 140617 (54.1%) Midlads 8396 (12.9%) 8556 (13.2%) 8423 (13.0%) 8724 (13.4%) 34099 (13.1%) South Eglad Norther Irelad Scotlad Wales 19648 (30.2%) 102 (0.2%) Yes 38656 (59.5%) Mea (SD) 9.40 (4.25) 0 to 1 2 to 4 5 to 9 10 12203 (18.8%) 15746 (24.2%) 16113 (24.8%) 20902 (32.2%) 21733 (33.4%) 38 (0.1%) 36148 (55.6%) 7.64 (4.26) 17940 (27.6%) 17056 (26.3%) 14454 (22.2%) 15523 (23.9%) 20616 (31.7%) 29 (0.0%) 37832 (58.2%) 9.05 (4.3) 21057 (32.4%) 17448 (26.9%) 13362 (20.6%) 13107 (20.2%) 22971 (35.4%) 23 (0.0%) 37616 (57.9%) 7.77 (4.4) 22445 (34.5%) 18262 (28.1%) 13186 (20.3%) 11072 (17.0%) 84968 (32.7%) 192 (0.1%) 150252 (57.8%) 8.46 (4.38) 73645 (28.3%) 68512 (26.4%) 57115 (22.0%) 60604 (23.3%)
Number of Healthcare resources utilizatio $ the year prior to referece date Mea (SD) 8.79 (10.21) 6.95 (9.07) 6.03 (8.41) 5.29 (7.24) 6.77 (8.9) Exposure to Live or Other vaccies i the year prior to the referece date Exposure to Live or Other vaccies i the 1 year follow-up period Yes 11435 (17.6%) Yes 10966 (16.9%) 11008 (16.9%) 9163 (14.1%) 10394 (16%) 42200 (16.2%) 7765 (12.0%) 7435 (11.4%) 6253 (9.6%) $ icludig e.g. GP cosultatios, prescriptios, ad laboratory tests Give the small umber of ovel adjuvated vacciees, oly Live ad Other vaccies were icluded SD=Stadard Deviatio Primary Outcome Results: Icidece rate of ew oset of autoimmue Kow date of first symptom Female Cohort Results No-Exposed Female Exposed Female cohort cohort Diseases Co-primary edpoits Neuroiflammatory/ Ophthalmic autoimmue (Tot PY=64705) Icidece [/100,000 PY] (95%CI) (Tot PY=64841) Icidece [/100,000 PY] (95%CI) 32419 (12.5%) Adjusted IRR* (95%CI) 0 0.00 (0.00; 5.70) 1 1.54 (0.04; 8.59) ND All 4 6.18 (1.68; 15.83) 7 10.80 (4.34; 22.24) 0.57 (0.17; 1.96) 58.73 (51.56; 38 Other autoimmue 80.61) 27 41.64 (27.44; 60.58) 1.41 (0.86; 2.31) 78.82 (58.69; All 51 103.63) 41 63.23 (45.38; 85.78) 1.25 (0.83; 1.88) Idividual with more tha 10 i Female cohorts 23.18 (12.98; 15 Autoimmue 38.24) 4 6.17 (1.68; 15.80) 3.75 (1.25; 11.31) thyroiditis Croh s disease Type 1 diabetes mellitus All 26 40.18 (26.25; 58.88) 18 27.76 (16.45; 43.87) 1.45 (0.79; 2.64) 6 9.27 (3.40; 20.18) 5 7.71 (2.50; 18.00) 1.21 (0.37; 3.95) All 8 12.36 (5.34; 24.26) 5 7.71 (2.50; 18.00) 1.61 (0.53; 4.91) 0.50 (0.21; 1.17) 8 12.36 (5.34; 24.36) 16 24.68 (14.10; 40.07) 0.30 (0.11; 0.83) $ All 8 12.36 (5.34; 24.36) 16 24.68 (14.10; 40.07) 0.50 (0.24; 1.17) Male Cohort Results Cocurret Male cohort Historical Male cohort (Tot PY=64859) (Tot PY=64868) Diseases Icidece [/100,000 PY] (95%CI) Icidece [/100,000 PY] (95%CI) Adjusted IRR* (95%CI) Co-primary edpoits
Neuroiflammatory/ Ophthalmic autoimmue 1 1.54 (0.04; 8.59) 1 1.54 (0.04; 8.59) 0.95 (0.06; 15.18) All 3 4.63 (0.95; 13.52) 2 3.08 (0.37; 11.14) 1.73 (0.29; 10.47) 40.09 (26.19; 26 Other autoimmue 58.74) 15 23.12 (12.94; 38.14) 1.77 (0.94; 3.35) 43.17 (28.69; All 28 62.39) 19 29.29 (17.64; 45.74) 1.52 (0.85; 2.73) Idividual with more tha 10 i Female cohorts Autoimmue 0 0.00 (0.00; 5.69) 0 0.00 (0.00; 5.69) ND thyroiditis All 2 3.08 (0.37; 11.14) 3 4.63 (0.95; 13.52) 0.76 (0.13; 4.60) Croh s disease 4 6.17 (1.68; 15.79) 1 1.54 (0.04; 8.59) 4.22 (0.47; 38.02) All 4 6.17 (1.68; 15.79) 2 3.08 (0.37;11.14) 2.06 (0.38; 11.34) 30.84 (18.84; Type 1 diabetes 20 8 12.33 (5.32; 24.30) 2.46 (1.08; 5.60) 47.62) mellitus 30.84 (18.84; All 20 8 12.33 (5.32; 24.30) 2.46 (1.08; 5.60) 47.62) ND= Not Doe; IRR*= Icidece Rate Ratio adjusted for age group [9-17]-[18-25]; $ - adjusted for the differece betwee male cohorts Secodary Outcome Results: Icidece rate of Juveile Rheumatoid Arthritis i Female Cohorts - Mai Aalysis - (Total cohort) Cohort Number of Perso-time (i years) Icidece Rate (per 100,000 PY) LL UL No-Exposed Female 0 64841 0.000 0.000 5.689 Secodary Outcome Results: Icidece rate of Multiple Sclerosis i Female Cohorts - Mai Aalysis - (Total cohort) Cohort Number of Perso-time (i years) Icidece Rate (per 100,000 PY) LL UL Exposed Female 0 64705 0.000 0.000 5.701 No-Exposed Female 1 64841 1.542 0.039 8.593 Secodary Outcome Results: Icidece rate of Psoriatic Arthritis i Female Cohorts - Mai Aalysis - (Total cohort) Cohort Number of Perso-time (i years) Icidece Rate (per 100,000 PY) LL UL No-Exposed Female 1 64841 1.542 0.039 8.593 Secodary Outcome Results: Icidece rate of Rheumatoid Arthritis i Female Cohorts - Mai Aalysis - (Total cohort) Cohort Number of Perso-time (i years) Icidece Rate (per 100,000 PY) LL UL No-Exposed Female 0 64841 0.000 0.000 5.689 Secodary Outcome Results: Icidece rate of Autoimmue Ulcerative Colitis i Female Cohorts - Mai Aalysis - (Total cohort) Cohort Number of Perso-time (i years) Icidece Rate (per 100,000 PY) LL UL Exposed Female 4 64705 6.182 1.684 15.828 No-Exposed Female 0 64841 0.000 0.000 5.689 Secodary Outcome Results: Icidece rate of Idiopathic Thrombocytopeia Purpura i Female Cohorts - Mai Aalysis - (Total cohort)
Cohort Number of Perso-time (i years) Icidece Rate (per 100,000 PY) LL UL No-Exposed Female 1 64841 1.542 0.039 8.593 Safety Results: Not applicable Coclusio: For the euroiflammatory/ophthalmic (cofirmed ), the adjusted Icidece Rate Ratio (IRR) for male cohorts was 0.95 [95%CI: 0.06-15.18] ad it was ot doe for females due to oly oe case i the No-exposed cohort. For the other autoimmue (cofirmed ), the adjusted IRRs were 1.41 [95%CI: 0.86-2.31] for the exposed ad o-exposed female cohorts ad 1.77 [95%CI: 0.94-3.35] for the cocurret ad historical male cohorts. For autoimmue (AI) thyroiditis, the IRR was 3.75 [95%CI: 1.25-11.31] for cofirmed i the two female cohorts meaig that the risk is higher i exposed wome ad the differece betwee exposed ad o-exposed wome was statistically sigificat. For type 1 diabetes, the IRR after adjustmet for male effect was 0.03 [95%CI: 0.30-0.83] for cofirmed i the female cohorts meaig that the risk is statistically lower i the exposed wome. The SCCS did ot fid ay sigificat IRR. Date updated: 16-Jue-2015