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.: 112022 (HPV-058) Title: Immunogenicity and safety of GlaxoSmithKline (GSK) Biologicals Human Papillomavirus (HPV) 580299 vaccine in healthy Chinese female subjects. Cervarix TM - GSK580299 (HPV): GSK Biologicals HPV vaccine containing HPV-16/18 L1 virus-like particles (VLPs). Rationale: The aim of this study was to evaluate the immunogenicity and safety of HPV in healthy Chinese pre-teen and adolescent female subjects aged 9-17 years. The immunogenicity in subjects aged 9-17 years would be compared with the immunogenicity seen in the Chinese subjects aged 18-25 years from the HPV-039 study (107638). Phase: III Study Period: 24 October 2009 to 08 December 2010 Study Design: Double-blind, controlled, randomized study with 2 parallel groups (1:1). Centers: 1 center in China Indication: Active immunization against persistent HPV-16 & HPV-18 infection and HPV-16 & HPV-18 infection associated cytological abnormalities, cervical intraepithelial neoplasia and precancerous lesions in females from 9 years of age onwards. Treatment: The study groups were as follows: : Subjects received 3 doses of HPV vaccine : Subjects received 3 doses of placebo. HPV vaccine and placebo were administered intramuscularly into the deltoid muscle of the non-dominant arm according to a 0, 1, 6-month schedule. Objectives: To demonstrate the non-inferiority of HPV immune response at one month post-dose 3 in Chinese female subjects aged 9-17 years from the current study versus Chinese women aged 18-25 years enrolled in study 107638 (HPV-039). Criterion for non-inferiority (one month after the third vaccine dose): - The objective was reached if for each HPV antigen (anti-hpv-16 and anti-hpv-18), the upper limit of the 95% confidence interval (CI) for the geometric mean titer (GMT) ratio [GMTs in subjects aged 18-25 years with immunogenicity results at Month 7 who received HPV vaccine in the 107638 (HPV-039) study divided by the GMTs of subjects aged 9-17 years who received HPV vaccine in the study 112022 (HPV-058)] was < 2. This objective was to be evaluated in the according-to-protocol (ATP) cohort for immunogenicity. Primary Outcome/Efficacy Variable: Evaluation of immune responses to components of the study vaccine, one month after the third dose (Month 7). - Antibody GMTs (by Enzyme-linked Immunosorbent Assay (ELISA)) against HPV-16/18 antigens. Secondary Outcome/Efficacy Variable(s): Immunogenicity: Immunogenicity in terms of the study vaccine antigens at Month 7. - HPV-16 and HPV-18 seroconversion at Month 7. Seroconversion is defined as the appearance of antibodies titer to the cut-off value (8 EL.U/mL for HPV-16 and 7 EL.U/mL for HPV-18) in the sera of subjects seronegative before vaccination. A seronegative subject is a subject with a titer < cut-off value. A seropositive subject is a subject with a titer cut-off value. Safety: Occurrence of each solicited adverse event (AE) during the 7 days (Days 0 6) after each vaccination and any vaccination - Local (any, grade 3) adverse events. - General (any, grade 3, related) adverse events. Occurrence of unsolicited AEs within 30 days (Days 0 29) after any vaccination. - Intensity and relationship to vaccination. Occurrence of serious adverse events (SAEs) throughout the study period (up to the telephone contact at Month 12). - Intensity and relationship to vaccination. Occurrence of medically significant conditions # throughout the study period (up to the telephone contact at Month 12) regardless of causal relationship to vaccination and intensity. # Medically significant conditions (MSCs) are defined as: AEs prompting emergency room or physician visits that are not (1)
related to common diseases or (2) routine visits for physical examination or vaccination, or SAEs that are not related to common diseases. Common diseases include: upper respiratory infections, sinusitis, pharyngitis, gastroenteritis, urinary tract infections, cervicovaginal yeast infections, menstrual cycle abnormalities and injury. Pregnancies and pregnancy outcomes. Statistical Methods: The analyses were performed on the Total Vaccinated cohort and on the According To Protocol (ATP) cohort for analysis of immunogenicity. - The Total Vaccinated cohort included all vaccinated subjects for whom data were available. - The ATP cohort for analysis of immunogenicity included all evaluable subjects (i.e. those meeting all eligibility criteria, complying with the procedures defined in the protocol, with no elimination criteria during the study) who had received 3 doses of the study vaccine or the placebo, and for whom data concerning immunogenicity measures were available. This cohort included subjects for whom assay results were available for antibodies against at least one study vaccine antigen component after vaccination. Analysis of Immunogenicity: The analysis was based on the ATP cohort for immunogenicity. Inferential analysis: The GMT ratios [GMTs in subjects aged 18-25 years with immunogenicity results at Month 7 who received HPV vaccine in the HPV-039 study divided by the GMTs of subjects aged 9-17 years who received HPV vaccine in the HPV-058 study] was computed for each antibody in the subset of subjects initially seronegative for the corresponding HPV type. If the upper limits of the 95% CI for these GMT ratios were below 2, one could conclude non-inferiority in terms of immune response to both vaccine antigens one month after the third dose in the current study to that of subjects aged 18-25 years who received the HPV vaccine in the HPV-039 study. Descriptive analysis: At each time point that a blood sample result was available, seropositivity/seroconversion rates for HPV-16 and HPV-18 antigens with exact 95% CI and GMT with 95% CI were calculated. Antibody titers below the cut-off of the assay were given an arbitrary value of half the cut-off for the purpose of GMT calculation. Analysis of safety: The analysis was performed on the Total Vaccinated cohort. The percentages of subjects reporting each individual solicited local and general symptom during the 7-day (Days 0 6) follow-up period after each vaccination dose were tabulated with exact 95% CI, per group. The same tabulation was performed for grade 3 solicited symptoms and for solicited general symptoms assessed by the investigator as causally related to vaccination. The percentages of subjects reporting at least one unsolicited AE classified by the Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms and reported up to 30 days (Days 0-29) after vaccination were tabulated per group. Grade 3 unsolicited AEs and unsolicited AEs assessed by the investigator as causally related to vaccination were also tabulated. The occurrence of medically significant conditions and SAEs throughout the entire study period was tabulated according to MedDRA preferred term. The occurrence of pregnancies was collected during the entire study period. Study Population: Healthy Chinese female subjects 9 to 17 years of age at the time of first vaccination without previous vaccination against HPV or previous administration of components of the study vaccine. Subjects were to be of nonchildbearing potential or, had to be abstinent or to practice adequate contraception for 30 days prior to the first vaccination, to have a negative pregnancy test before each vaccination and had agreed to continue such precautions for 2 months after completion of the vaccination series. Written informed consent was obtained from the parent / legally acceptable representative of the subject and informed assent obtained from the subject, if appropriate, prior to enrolment. Number of subjects Planned, N 375 375 Randomized, N (Total Vaccinated cohort) 374 376 Completed, n (%) 369 (98.7) 365 (97.1) Total Number Subjects Withdrawn, n (%) 5 (1.3) 11 (2.9) Withdrawn due to Adverse Events, n (%) 0 (0.0) 2 (0.5) Withdrawn due to Lack of Efficacy, n (%) Not applicable Not applicable Withdrawn for other reasons, n (%) 5 (1.3) 9 (2.4) Demographics N (Total Vaccinated cohort) 374 376 Females: Males 374:0 376:0 Mean Age, years (SD) 13.1 (2.44) 13.1 (2.42) Asian - Chinese heritage, n (%) 374 (100) 376 (100)
Primary Efficacy Results: Non-inferiority assessment of HPV immune response in Chinese female subjects aged 9-17 years from the current study (HPV-058) versus Chinese women aged 18-25 years enrolled in the HPV-039 study, 1 month Post Dose III (ATP cohort for immunogenicity) Antibody HPV-039 HPV-058 GMT ratio (HPV-039 / HPV-058) 95% CI N GMT N GMT Value LL UL* HPV-16 244 6996.2 326 18682.4 0.37 0.32 0.43 HPV-18 289 3309.4 338 7882.4 0.42 0.36 0.49 GMT = geometric mean antibody titer N = Number of subjects with post-vaccination results available 95% CI = 95% confidence interval for the GMC ratio LL = lower limit, UL = upper limit *Non-inferiority criterion: UL of 95%CI for the GMT ratio (HPV-039/HPV-058) < 2 Primary Efficacy Results: Seropositivity rates, seroconversion rates and GMTs for anti-hpv-16 antibodies by pre-vaccination status (ATP cohort for immunogenicity) Antibody Group Pre-vacc status Timing N 8 EL.U/mL GMT* 95% CI Value 95% CI n % LL UL LL UL HPV-16 HPV S- PRE 326 0 0.0 0.0 1.1 4.0 4.0 4.0 PIII(M7) 326 326 100 98.9 100 18682.4 17162.7 20336.6 S+ PRE 36 36 100 90.3 100 19.9 16.6 23.8 PIII(M7) 36 36 100 90.3 100 15571.9 11700.0 20725.3 Total PRE 362 36 9.9 7.1 13.5 4.7 4.5 4.9 PIII(M7) 362 362 100 99.0 100 18347.1 16915.2 19900.2 Control S- PRE 323 0 0.0 0.0 1.1 4.0 4.0 4.0 PIII(M7) 323 8 2.5 1.1 4.8 4.1 4.0 4.2 S+ PRE 40 40 100 91.2 100 21.6 17.1 27.4 PIII(M7) 40 38 95.0 83.1 99.4 22.2 16.3 30.1 Total PRE 363 40 11.0 8.0 14.7 4.8 4.5 5.1 PIII(M7) 363 46 12.7 9.4 16.5 5.0 4.7 5.3 S- = seronegative subjects (antibody concentration < 8 EL.U/mL) prior to vaccination S+ = seropositive subjects (antibody concentration 8 EL.U/mL) prior to vaccination Seroconversion defined as the appearance of antibodies titer 8 EL.U/mL in the sera of subjects seronegative before vaccination. GMT = geometric mean antibody titer calculated on all subjects N = number of subjects with pre-vaccination results available n/% = number/percentage of subjects with concentration within the specified range 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit PRE =Prevaccination PIII(M7) =Post Dose III (Month 7) *Primary outcome variable Primary Efficacy Results: Seropositivity rates, seroconversion rates and GMTs for anti-hpv-18 antibodies by pre-vaccination status (ATP cohort for immunogenicity) Antibody Group Pre-vacc status Timing N 7 EL.U/mL GMT* 95% CI Value 95% CI n % LL UL LL UL HPV-18 HPV S- PRE 338 0 0.0 0.0 1.1 3.5 3.5 3.5 PIII(M7) 338 336 99.4 97.9 99.9 7882.4 7079.0 8777.1 S+ PRE 24 24 100 85.8 100 21.9 16.8 28.5 PIII(M7) 24 24 100 85.8 100 9140.0 6318.3 13221.8 Total PRE 362 24 6.6 4.3 9.7 4.0 3.8 4.2 PIII(M7) 362 360 99.4 98.0 99.9 7960.2 7181.3 8823.6 Control S- PRE 344 0 0.0 0.0 1.1 3.5 3.5 3.5 PIII(M7) 344 10 2.9 1.4 5.3 3.7 3.6 3.8 S+ PRE 19 19 100 82.4 100 18.4 13.4 25.3 PIII(M7) 19 18 94.7 74.0 99.9 22.4 15.4 32.7
Total PRE 363 19 5.2 3.2 8.1 3.8 3.7 4.0 PIII(M7) 363 28 7.7 5.2 11.0 4.1 3.8 4.3 S- = seronegative subjects (antibody concentration < 7 EL.U/mL) prior to vaccination S+ = seropositive subjects (antibody concentration 7 EL.U/mL) prior to vaccination Seroconversion defined as the appearance of antibodies titer 7 EL.U/mL in the sera of subjects seronegative before vaccination. GMT = geometric mean antibody titer calculated on all subjects N = number of subjects with pre-vaccination results available n/% = number/percentage of subjects with concentration within the specified range 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit PRE =Prevaccination PIII(M7) =Post Dose III (Month 7) *Primary outcome variable Secondary Outcome Variable(s): Incidence of solicited local symptoms reported during the 7-day (Days 0-6) postvaccination period following each dose and across doses (Total Vaccinated cohort) Symptom Intensity N n % 95 % CI N n % 95 % CI LL UL LL UL Dose 1 Pain Any 373 329 88.2 84.5 91.3 376 265 70.5 65.6 75.0 Grade 3 373 14 3.8 2.1 6.2 376 8 2.1 0.9 4.1 Redness Any 373 61 16.4 12.7 20.5 376 30 8.0 5.4 11.2 >50 mm 373 0 0.0 0.0 1.0 376 1 0.3 0.0 1.5 Swelling Any 373 51 13.7 10.4 17.6 376 30 8.0 5.4 11.2 >50 mm 373 7 1.9 0.8 3.8 376 2 0.5 0.1 1.9 Dose 2 Pain Any 372 275 73.9 69.1 78.3 375 183 48.8 43.6 54.0 Grade 3 372 13 3.5 1.9 5.9 375 4 1.1 0.3 2.7 Redness Any 372 41 11.0 8.0 14.7 375 20 5.3 3.3 8.1 >50 mm 372 1 0.3 0.0 1.5 375 0 0.0 0.0 1.0 Swelling Any 372 47 12.6 9.4 16.4 375 15 4.0 2.3 6.5 >50 mm 372 3 0.8 0.2 2.3 375 0 0.0 0.0 1.0 Dose 3 Pain Any 368 251 68.2 63.2 72.9 365 167 45.8 40.6 51.0 Grade 3 368 18 4.9 2.9 7.6 365 8 2.2 1.0 4.3 Redness Any 368 65 17.7 13.9 22.0 365 22 6.0 3.8 9.0 >50 mm 368 1 0.3 0.0 1.5 365 0 0.0 0.0 1.0 Swelling Any 368 71 19.3 15.4 23.7 365 22 6.0 3.8 9.0 >50 mm 368 6 1.6 0.6 3.5 365 0 0.0 0.0 1.0 Across Doses Pain Any 373 350 93.8 90.9 96.1 376 299 79.5 75.1 83.5 Grade 3 373 38 10.2 7.3 13.7 376 16 4.3 2.5 6.8 Redness Any 373 113 30.3 25.7 35.2 376 52 13.8 10.5 17.7 >50 mm 373 2 0.5 0.1 1.9 376 1 0.3 0.0 1.5 Swelling Any 373 113 30.3 25.7 35.2 376 54 14.4 11.0 18.3 >50 mm 373 13 3.5 1.9 5.9 376 2 0.5 0.1 1.9 N= number of subjects with at least one documented dose n (%) = number (percentage) of subjects reporting the symptom at least once 95% CI = exact 95% confidence interval; LL = lower limit, UL = upper limit Any = any solicited local symptom reported irrespective of intensity Grade 3 Pain = pain that prevented normal activity Secondary Outcome Variable(s): Incidence of solicited general symptoms reported during the 7-day (Days 0-6) postvaccination period following each dose and across doses (Total Vaccinated cohort) Symptom Intensity / Relationship N n % 95 % CI N n % 95 % CI LL UL LL UL
Dose 1 Arthralgia Any 373 27 7.2 4.8 10.4 376 23 6.1 3.9 9.0 Grade 3 373 0 0.0 0.0 1.0 376 1 0.3 0.0 1.5 Related 373 21 5.6 3.5 8.5 376 16 4.3 2.5 6.8 Fatigue Any 373 92 24.7 20.4 29.4 376 98 26.1 21.7 30.8 Grade 3 373 1 0.3 0.0 1.5 376 4 1.1 0.3 2.7 Related 373 72 19.3 15.4 23.7 376 75 19.9 16.0 24.3 Gastrointestinal Any 373 41 11.0 8.0 14.6 376 33 8.8 6.1 12.1 Grade 3 373 2 0.5 0.1 1.9 376 2 0.5 0.1 1.9 Related 373 16 4.3 2.5 6.9 376 23 6.1 3.9 9.0 Headache Any 373 74 19.8 15.9 24.3 376 66 17.6 13.8 21.8 Grade 3 373 2 0.5 0.1 1.9 376 3 0.8 0.2 2.3 Related 373 52 13.9 10.6 17.9 376 49 13.0 9.8 16.9 Myalgia Any 373 80 21.4 17.4 26.0 376 68 18.1 14.3 22.4 Grade 3 373 1 0.3 0.0 1.5 376 0 0.0 0.0 1.0 Related 373 67 18.0 14.2 22.2 376 64 17.0 13.4 21.2 Rash Any 373 6 1.6 0.6 3.5 376 1 0.3 0.0 1.5 Grade 3 373 0 0.0 0.0 1.0 376 0 0.0 0.0 1.0 Related 373 1 0.3 0.0 1.5 376 0 0.0 0.0 1.0 Fever/(Axillary) > 37.0 C 373 35 9.4 6.6 12.8 376 28 7.4 5.0 10.6 > 39.0 C 373 1 0.3 0.0 1.5 376 0 0.0 0.0 1.0 Related 373 25 6.7 4.4 9.7 376 13 3.5 1.9 5.8 Urticaria Any 373 5 1.3 0.4 3.1 376 2 0.5 0.1 1.9 Grade 3 373 0 0.0 0.0 1.0 376 0 0.0 0.0 1.0 Related 373 4 1.1 0.3 2.7 376 0 0.0 0.0 1.0 Dose 2 Arthralgia Any 372 6 1.6 0.6 3.5 375 7 1.9 0.8 3.8 Related 372 1 0.3 0.0 1.5 375 6 1.6 0.6 3.4 Fatigue Any 372 50 13.4 10.1 17.3 375 35 9.3 6.6 12.7 Related 372 28 7.5 5.1 10.7 375 23 6.1 3.9 9.1 Gastrointestinal Any 372 14 3.8 2.1 6.2 375 14 3.7 2.1 6.2 Related 372 5 1.3 0.4 3.1 375 8 2.1 0.9 4.2 Headache Any 372 46 12.4 9.2 16.1 375 33 8.8 6.1 12.1 Grade 3 372 1 0.3 0.0 1.5 375 0 0.0 0.0 1.0 Related 372 20 5.4 3.3 8.2 375 18 4.8 2.9 7.5 Myalgia Any 372 47 12.6 9.4 16.4 375 32 8.5 5.9 11.8 Related 372 33 8.9 6.2 12.2 375 24 6.4 4.1 9.4 Rash Any 372 1 0.3 0.0 1.5 375 1 0.3 0.0 1.5 Related 372 1 0.3 0.0 1.5 375 1 0.3 0.0 1.5 Fever/(Axillary) > 37.0 C 372 30 8.1 5.5 11.3 375 27 7.2 4.8 10.3 > 39.0 C 372 1 0.3 0.0 1.5 375 0 0.0 0.0 1.0 Related 372 9 2.4 1.1 4.5 375 4 1.1 0.3 2.7 Urticaria Any 372 4 1.1 0.3 2.7 375 1 0.3 0.0 1.5 Related 372 2 0.5 0.1 1.9 375 1 0.3 0.0 1.5 Dose 3 Arthralgia Any 368 9 2.4 1.1 4.6 365 5 1.4 0.4 3.2 Grade 3 368 0 0.0 0.0 1.0 365 1 0.3 0.0 1.5 Related 368 6 1.6 0.6 3.5 365 2 0.5 0.1 2.0 Fatigue Any 368 56 15.2 11.7 19.3 365 47 12.9 9.6 16.8
Grade 3 368 1 0.3 0.0 1.5 365 0 0.0 0.0 1.0 Related 368 31 8.4 5.8 11.7 365 24 6.6 4.3 9.6 Gastrointestinal Any 368 15 4.1 2.3 6.6 365 7 1.9 0.8 3.9 Grade 3 368 0 0.0 0.0 1.0 365 0 0.0 0.0 1.0 Related 368 6 1.6 0.6 3.5 365 2 0.5 0.1 2.0 Headache Any 368 48 13.0 9.8 16.9 365 32 8.8 6.1 12.2 Grade 3 368 2 0.5 0.1 1.9 365 0 0.0 0.0 1.0 Related 368 27 7.3 4.9 10.5 365 14 3.8 2.1 6.4 Myalgia Any 368 35 9.5 6.7 13.0 365 30 8.2 5.6 11.5 Grade 3 368 0 0.0 0.0 1.0 365 1 0.3 0.0 1.5 Related 368 28 7.6 5.1 10.8 365 18 4.9 2.9 7.7 Rash Any 368 2 0.5 0.1 1.9 365 2 0.5 0.1 2.0 Grade 3 368 0 0.0 0.0 1.0 365 0 0.0 0.0 1.0 Related 368 1 0.3 0.0 1.5 365 1 0.3 0.0 1.5 Fever/(Axillary) > 37.0 C 368 31 8.4 5.8 11.7 365 30 8.2 5.6 11.5 > 39.0 C 368 0 0.0 0.0 1.0 365 0 0.0 0.0 1.0 Related 368 8 2.2 0.9 4.2 365 10 2.7 1.3 5.0 Urticaria Any 368 2 0.5 0.1 1.9 365 2 0.5 0.1 2.0 Grade 3 368 0 0.0 0.0 1.0 365 0 0.0 0.0 1.0 Related 368 2 0.5 0.1 1.9 365 0 0.0 0.0 1.0 Across Doses Arthralgia Any 373 38 10.2 7.3 13.7 376 33 8.8 6.1 12.1 Grade 3 373 0 0.0 0.0 1.0 376 2 0.5 0.1 1.9 Related 373 25 6.7 4.4 9.7 376 23 6.1 3.9 9.0 Fatigue Any 373 137 36.7 31.8 41.8 376 126 33.5 28.8 38.5 Grade 3 373 2 0.5 0.1 1.9 376 4 1.1 0.3 2.7 Related 373 106 28.4 23.9 33.3 376 98 26.1 21.7 30.8 Gastrointestinal Any 373 57 15.3 11.8 19.3 376 45 12.0 8.9 15.7 Grade 3 373 2 0.5 0.1 1.9 376 2 0.5 0.1 1.9 Related 373 21 5.6 3.5 8.5 376 31 8.2 5.7 11.5 Headache Any 373 123 33.0 28.2 38.0 376 99 26.3 21.9 31.1 Grade 3 373 5 1.3 0.4 3.1 376 3 0.8 0.2 2.3 Related 373 80 21.4 17.4 26.0 376 70 18.6 14.8 22.9 Myalgia Any 373 110 29.5 24.9 34.4 376 93 24.7 20.5 29.4 Grade 3 373 1 0.3 0.0 1.5 376 1 0.3 0.0 1.5 Related 373 96 25.7 21.4 30.5 376 83 22.1 18.0 26.6 Rash Any 373 9 2.4 1.1 4.5 376 4 1.1 0.3 2.7 Grade 3 373 0 0.0 0.0 1.0 376 0 0.0 0.0 1.0 Related 373 3 0.8 0.2 2.3 376 2 0.5 0.1 1.9 Fever/(Axillary) > 37.0 C 373 86 23.1 18.9 27.7 376 74 19.7 15.8 24.1 > 39.0 C 373 2 0.5 0.1 1.9 376 0 0.0 0.0 1.0 Related 373 40 10.7 7.8 14.3 376 27 7.2 4.8 10.3 Urticaria Any 373 8 2.1 0.9 4.2 376 3 0.8 0.2 2.3 Grade 3 373 0 0.0 0.0 1.0 376 0 0.0 0.0 1.0 Related 373 7 1.9 0.8 3.8 376 1 0.3 0.0 1.5 N= number of subjects with at least one documented dose n (%) = number (percentage)of subjects reporting the symptom at least once 95%CI= exact 95% confidence interval; LL = lower limit, UL = upper limit Any = any solicited general symptom reported irrespective of intensity and relationship to vaccination Related = symptoms considered by the investigator to have a causal relationship to vaccination Grade 3 Symptoms = symptoms that prevented normal activity Grade 3 Urticaria = urticaria distributed on at least 4 body areas
Secondary Outcome Variable(s): Number (%) of subjects with medically significant conditions (MSCs) during the entire study period (Total Vaccinated cohort) MSCs N = 376 N = 374 Subjects with any MSC(s), n (%) 14 (3.7) 11 (2.9) Diarrhoea 3 (0.8) - Pyrexia 1 (0.3) 2 (0.5) Henoch-schonlein purpura - 2 (0.5) Abdominal adhesions 1 (0.3) - Abdominal pain upper - 1 (0.3) Adnexa uteri cyst 1 (0.3) - Animal bite - 1 (0.3) Bronchopneumonia 1 (0.3) - Cough 1 (0.3) - Epistaxis 1 (0.3) - Food poisoning 1 (0.3) - Hand fracture - 1 (0.3) Lymphadenopathy 1 (0.3) - Menorrhagia - 1 (0.3) Multiple fractures - 1 (0.3) Pain in extremity 1 (0.3) - Skin papilloma 1 (0.3) - Tinea infection - 1 (0.3) Tinea pedis - 1 (0.3) Ulna fracture - 1 (0.3) Upper motor neurone lesion 1 (0.3) - Varicella - 1 (0.3) - : MSC absent Secondary Outcome Variable(s): No pregnancies were reported during the entire study period. Safety results: Number (%) of subjects with unsolicited adverse events within 30 days (Days 0 29) after any vaccination (Total Vaccinated cohort) Most frequent adverse events - On-Therapy (occurring within Days 0-29 following vaccination) N = 374 N = 376 Subjects with any AE(s), n (%) 139 (37.2) 125 (33.2) Subjects with grade 3 AE(s), n (%) 0 (0.0) 3 (0.8) Subjects with related AE(s), n (%) 2 (0.5) 3 (0.8) Upper respiratory tract infection 101 (27.0) 86 (22.9) Nasopharyngitis 22 (5.9) 18 (4.8) Diarrhoea 4 (1.1) 2 (0.5) Cough 3 (0.8) 1 (0.3) Oropharyngeal pain - 3 (0.8) Pharyngitis 2 (0.5) 1 (0.3) Pyrexia 1 (0.3) 2 (0.5) Mouth ulceration 2 (0.5) - Pain in extremity 2 (0.5) - Rhinitis 2 (0.5) - Tonsillitis 2 (0.5) - Varicella - 2 (0.5) Abdominal distension 1 (0.3) - Abdominal pain upper - 1 (0.3) Angina pectoris 1 (0.3) - Animal bite - 1 (0.3) Arthralgia - 1 (0.3) Bronchopneumonia 1 (0.3) - Contusion 1 (0.3) - Dizziness - 1 (0.3)
Frostbite 1 (0.3) - Gastroenteritis 1 (0.3) - Gingivitis - 1 (0.3) Haematoma - 1 (0.3) Headache 1 (0.3) - Henoch-schonlein purpura - 1 (0.3) Injection site haematoma - 1 (0.3) Ligament injury - 1 (0.3) Menorrhagia - 1 (0.3) Multiple fractures - 1 (0.3) Nasal obstruction - 1 (0.3) Sinusitis 1 (0.3) - Skin mass 1 (0.3) - Thermal burn 1 (0.3) - Tinea infection - 1 (0.3) Tinea pedis - 1 (0.3) Upper motor neurone lesion 1 (0.3) - Vessel puncture site reaction - 1 (0.3) Vitamin b1 deficiency 1 (0.3) - - : Adverse event absent Grade 3= event that prevented normal activity Related= event assessed by the investigator as causally related to the study vaccination. Safety results: Number (%) of subjects with serious adverse events during the entire study period (Total Vaccinated cohort) Serious adverse event, n (%) [n considered by the investigator to be related to study medication] All SAEs N = 374 N = 376 Subjects with any SAE(s), n (%) [n assessed by the investigator as 5 (1.3) [0] 2 (0.5) [0] related] Abdominal adhesions 1 (0.3) [0] 0 (0.0) [0] Adnexa uteri cyst 1 (0.3) [0] 0 (0.0) [0] Bronchopneumonia 1 (0.3) [0] 0 (0.0) [0] Food poisoning 1 (0.3) [0] 0 (0.0) [0] Hand fracture 0 (0.0) [0] 1 (0.3) [0] Lymphadenopathy 1 (0.3) [0] 0 (0.0) [0] Multiple fractures 0 (0.0) [0] 1 (0.3) [0] Ulna fracture 0 (0.0) [0] 1 (0.3) [0] Fatal SAEs Subjects with fatal SAE(s), n (%) [n assessed by the investigator as related] N = 374 N = 376 0 (0.0) [0] 0 (0.0) [0] Conclusion: One month after the third vaccine dose, the GMT values for anti-hpv-16 and anti-hpv-18 antibodies were, respectively, 18682.4 and 7882.4 in initially seronegative Chinese female subjects aged 9-17 years from the current study (HPV-058), and were 6996.2 and 3309.4 in initially seronegative Chinese women aged 18-25 years enrolled in the HPV-039 study. During the 30-day follow-up period after vaccination, at least one unsolicited adverse event was reported for 139 (37.2%) and 125 (33.2%) subjects in the HPV and Control groups, respectively. During the entire study period, up to Month 12, at least one SAE was reported for 5 (1.3%) subjects in the and 2 (0.5%) subjects in the. None of these SAEs were fatal and all were assessed by the investigators as not causally related to the study vaccination. Date updated: 08-December-2014