Study No.: Title: Rationale: Phase: Study Period: Study Design: Centers: Indication Treatment: Objectives: Primary Outcome/Efficacy Variable:

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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 No.: (HPV-058) Title: Immunogenicity and safety of GlaxoSmithKline (GSK) Biologicals Human Papillomavirus (HPV) vaccine in healthy Chinese female subjects. Cervarix TM - GSK (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 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 years enrolled in study (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 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 study (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)

2 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 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 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 Randomized, N (Total Vaccinated cohort) 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) 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)

3 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 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 HPV 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 PIII(M7) S+ PRE PIII(M7) Total PRE PIII(M7) Control S- PRE PIII(M7) S+ PRE PIII(M7) Total PRE PIII(M7) 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 PIII(M7) S+ PRE PIII(M7) Total PRE PIII(M7) Control S- PRE PIII(M7) S+ PRE PIII(M7)

4 Total PRE PIII(M7) 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 Grade Redness Any >50 mm Swelling Any >50 mm Dose 2 Pain Any Grade Redness Any >50 mm Swelling Any >50 mm Dose 3 Pain Any Grade Redness Any >50 mm Swelling Any >50 mm Across Doses Pain Any Grade Redness Any >50 mm Swelling Any >50 mm 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

5 Dose 1 Arthralgia Any Grade Related Fatigue Any Grade Related Gastrointestinal Any Grade Related Headache Any Grade Related Myalgia Any Grade Related Rash Any Grade Related Fever/(Axillary) > 37.0 C > 39.0 C Related Urticaria Any Grade Related Dose 2 Arthralgia Any Related Fatigue Any Related Gastrointestinal Any Related Headache Any Grade Related Myalgia Any Related Rash Any Related Fever/(Axillary) > 37.0 C > 39.0 C Related Urticaria Any Related Dose 3 Arthralgia Any Grade Related Fatigue Any

6 Grade Related Gastrointestinal Any Grade Related Headache Any Grade Related Myalgia Any Grade Related Rash Any Grade Related Fever/(Axillary) > 37.0 C > 39.0 C Related Urticaria Any Grade Related Across Doses Arthralgia Any Grade Related Fatigue Any Grade Related Gastrointestinal Any Grade Related Headache Any Grade Related Myalgia Any Grade Related Rash Any Grade Related Fever/(Axillary) > 37.0 C > 39.0 C Related Urticaria Any Grade Related 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

7 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)

8 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 = (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, and in initially seronegative Chinese female subjects aged 9-17 years from the current study (HPV-058), and were and in initially seronegative Chinese women aged 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