Study No.: Title: Rationale: Phase: Study Period: Study Design: Centres: 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.: (MenACWY-TT-093) Title: Immunogenicity and safety study of one dose of GSK Biologicals meningococcal vaccine GSK (blinded lots) versus one dose of Mencevax ACWY in healthy subjects aged years Nimenrix - GSK (MenACWY-TT): GlaxoSmithKline (GSK) Biologicals meningococcal serogroups A, C, W-135, Y tetanus toxoid conjugate vaccine. Mencevax ACWY (MenACWY): GSK Biologicals meningococcal serogroups A, C, W-135 and Y plain polysaccharide vaccine. Rationale: The aim of this study was to evaluate the immunogenicity and safety as well as the non-inferiority of the MenACWY-TT conjugate vaccine using the MenACWY vaccine as control in healthy subjects. In addition, this study aimed to compare the immunogenicity between 2 lots of the MenACWY-TT vaccine. Phase: III Study Period: 27 August 2010 to 30 December 2010 Study Design: Randomized (1:1:1), partially-blinded*, controlled, multi-centre study with 3 parallel groups. *The study design was observer blinded with respect to lots of MenACWY-TT and open with respect to MenACWY-TT or MenACWY due to different route of injection. Centres: 3 centres (1 in Panama, 1 in Thailand and 1 in the Philippines). Indication: Immunisation against meningococcal serogroups A, C, W-135 and Y diseases in healthy adults between years of age. Treatment: The study groups were as follows: : subjects received a single dose of MenACWY-TT Lot A vaccine : subjects received a single dose of MenACWY-TT Lot B vaccine Control : subjects received a single dose of MenACWY vaccine MenACWY-TT vaccine was administered by intramuscular injection in the deltoid region of the non-dominant arm. MenACWY vaccine was administered by subcutaneous injection in the upper region of the non-dominant arm. Objectives: The co-primary objectives were assessed in a hierarchical manner according to the order presented below. A co-primary objective could only be met if the statistical criteria for that objective were met as well as the statistical criteria for all previous co-primary objectives. At 1 month after primary vaccination with MenACWY-TT Lot A, Lot B or MenACWY: To demonstrate the non-inferiority of the vaccine response* induced by MenACWY-TT conjugate vaccine (MenACWY-TT Lot A) when compared to the licensed MenACWY for Neisseria meningitidis (N. meningitidis) serogroups A, C, W-135 and Y as measured by serum bactericidal antibodies using baby rabbit complement (rsba) at GSK**. Criterion for non-inferiority: For each serogroup separately, the lower limit of the 2-sided standardised asymptotic 95% confidence interval (CI) for the group difference (MenACWY-TT Lot A minus MenACWY) in the percentage of subjects with bactericidal vaccine response would be greater than or equal to the pre-defined clinical limit of -10%. *Vaccine response was defined as an rsba titre of at least 1:32 in subjects initially seronegative [rsba titre <1:8] and as a 4- fold increase in titre from pre- to post-vaccination in subjects initially seropositive [rsba titre 1:8]. **GSK assay: The cut-off of the assay was a dilution of 1:8. Titres were expressed as the reciprocal of the exact dilution resulting in 50% inhibition. All subjects underwent testing with the GSK rsba assay for all 4 serogroups. To demonstrate the comparability of the immunogenicity of Lot A to Lot B of MenACWY-TT conjugate vaccine with respect to rsba geometric mean titres (GMTs) for N. meningitidis serogroups A, C, W-135, and Y, 1 month after vaccination as measured at GSK. Criterion for non-inferiority: Non-inferiority of MenACWY-TT Lot B vs. MenACWY-TT Lot A in terms of non-inferiority would be demonstrated if the upper limit of the 2-sided 95% CIs on the rsba GMT ratios (GMTs of MenACWY-TT Lot B over the GMTs of the MenACWY-TT Lot A) would be below a limit of 2-fold for antibodies against all meningococcal serogroups. Primary Outcome/Efficacy Variable: Immunogenicity in all subjects with respect to components of the investigational vaccine and the control vaccine: rsba-mena, rsba-menc, rsba-menw-135, rsba-meny vaccine response* in the and Control groups

2 using GSK assay. rsba-mena, rsba-menc, rsba-menw-135, rsba-meny GMTs 1 month after vaccination in the and groups using GSK assay. Secondary Outcome/Efficacy Variable(s): Immunogenicity in all subjects with respect to components of the investigational vaccines and the control vaccine (on secondary readouts): - rsba-mena, rsba-menc, rsba-menw-135 and rsba-meny, titres 1:8, 1:128, and GMTs prior to and 1 month after vaccination as measured by the Health Protection Agency (HPA)* in the and Control groups. - rsba-mena, rsba-menc, rsba-menw-135, rsba-meny titres 1:8, 1:128, and GMTs prior to and 1 month after vaccination as measured by GSK in the,, and Control groups except for those specified as primary endpoints. - rsba MenA, rsba MenC, rsba-menw-135, and rsba MenY vaccine response as measured by GSK in the and as measured by HPA in the and Control groups. - Anti-Polysaccharide N. meningitidis serogroup A (PSA), anti-psc, anti-psw-135, anti-psy antibody concentrations 0.3 μg/ml, 2.0 μg/ml and geometric mean concentration (GMCs) (in 50% of subjects) prior to and 1 month after vaccination #. Solicited local and general symptoms - Occurrence of each solicited local (any and grade 3) and general symptom (any, grade 3, related) on Days 0-3 following vaccination. Unsolicited adverse events - Occurrence of unsolicited non-serious and serious events, and new onset chronic illness (NOCI) (e.g., autoimmune disorders, asthma, type I diabetes and allergies) within 31 days (Day 0 Day 30) after vaccination, according to the Medical Dictionary for Regulatory Activities (MedDRA) classification. *HPA assay: The cut-off of the assay was a dilution of 1:4. Titres were expressed as the reciprocal of the highest dilution resulting in at least 50% inhibition. # Analysis was cancelled. Statistical Methods: The analyses were performed on the Total Vaccinated cohort for safety and the According-to-Protocol (ATP) cohort for immunogenicity : - The Total Vaccinated cohort included all vaccinated subjects for whom data were available. - The ATP cohort for immunogenicity included all evaluable subjects (i.e. those meeting all eligibility criteria, complying with the procedures defined in the protocol, and with no elimination criteria during the study), who had received the dose of study vaccine, for whom the administration site of the vaccine was known, who had not received a vaccine not specified or forbidden in the protocol, for whom assay results were available for antibodies against at least one study vaccine antigen component for the blood sample taken one month after vaccination. Immunogenicity The analysis of immunogenicity was performed on the ATP cohort for immunogenicity. Non-inferiority of compared to Control with respect to rsba MenA, MenC, MenW-135 and MenY vaccine response was evaluated by computing the asymptotic standardised 95% CIs for the difference in the percentage of subjects with rsba vaccine response ( rate minus Control rate) one month after vaccination, using GSK assay. Clinical comparability of compared to with respect to rsba MenA, MenC, MenW-135 and MenY GMTs was evaluated by computing the 95% CIs for the adjusted rsba GMT ratios between and (over). Adjusted GMT ratios were computed in using an ANCOVA model including the vaccine group as fixed effect and using the baseline titres and the country as covariates, and based on GSK assay results. The percentage of subjects with rsba titres equal or above the cut-off values (1:8 and 1:128), the percentage of subjects with vaccine response for rsba antibodies and the GMTs were calculated with 95% CIs for the 3 groups using GSK assay. The same tabulation was performed for and Control based on HPA assay results. Safety The analysis of safety was performed on the Total Vaccinated cohort. The percentages of subjects reporting individual solicited local and general symptoms during the 4-day (Days 0-3) follow-up period were tabulated per group with exact 95% CI. The same tabulation was done for grade 3 symptoms and for solicited general symptoms assessed by the investigators as related to the vaccination. The percentage of subjects with at least one report of unsolicited adverse events (AEs) classified by MedDRA preferred terms

3 and reported during the 31-day (Days 0-30) post-vaccination follow-up period was tabulated. The same tabulation was done for NOCIs. SAEs collected during the 31-day follow-up period and classified by MedDRA preferred terms were summarized. Study Population: Healthy male and female subjects between, and including, 18 and 25 years of age at the time of the vaccination with neither previous administration of meningococcal polysaccharide vaccine within the last 5 years, nor previous administration of meningococcal conjugate vaccine, nor previous vaccination with tetanus-toxoid or tetanus toxoid containing vaccine within the last month were included in this study. Female subjects of childbearing potential could be enrolled in the study, if the subject had practiced adequate contraception for 30 days prior to vaccination, had a negative pregnancy test on the day of vaccination and had agreed to continue adequate contraception during the entire treatment period and for 2 months after vaccination. Written informed consent was obtained from the subject prior to any study procedure. Number of subjects Control Planned, N Randomised, N (Total Vaccinated Cohort) Completed, n (%) 386 (99.0) 384 (98.5) 383 (98.2) Total Number Subjects Withdrawn, n (%) 4 (1.0) 6 (1.5) 7 (1.8) Withdrawn due to adverse events, n (%) 0 (0.0) 0 (0.0) 0 (0.0) Withdrawn due to Lack of Efficacy n (%) Not Applicable Not Applicable Not Applicable Withdrawn for other reasons n (%) 4 (1.0) 6 (1.5) 7 (1.8) Demographics Control N (Total Vaccinated Cohort) Females:Males 197: : :186 Mean Age, years (SD) 20.8 (2.14) 20.9 (2.10) 20.6 (1.94) Asian - South East Asian heritage, n (%) 258 (66.2) 259 (66.4) 257 (65.9) Primary Efficacy Results: Difference between and Control groups in percentage of subjects with vaccine response to rsba antibodies 1 month after vaccination, GSK rsba assay (ATP cohort for immunogenicity) Difference in vaccine response rate ( minus Control ) Control % 95% CI Antibody N n % N n % LL* UL rsba-mena rsba-menc rsba-menw rsba-meny Vaccine response defined as: For initially seronegative subjects, antibody titre 1:32 at PI(M1) For initially seropositive subjects: antibody titre at PI(M1) 4 fold the pre-vaccination antibody titre n/% = number/percentage of subjects with titre within the specified range 95% CI = Standardized asymptotic 95% confidence interval; LL = lower limit, UL = upper limit *Non-inferiority criterion: LL of the 2-sided 95% CI for the group difference ( minus Control ) in the percentage of subjects with vaccine response -10%. Primary Efficacy Results: Adjusted GMT ratios between and groups for rsba-mena, rsba- MenC, rsba-menw-135, rsba-meny titres 1 month after vaccination, GSK rsba assay (ATP cohort for immunogenicity) Adjusted GMT ratio ( / ) Value 95% CI Antibody N Adjusted GMT N Adjusted GMT LL UL* rsba-mena rsba-menc rsba-menw rsba-meny Adjusted GMT = geometric mean antibody titre adjusted for country, baseline titre

4 95% CI = 95% confidence interval for the adjusted GMT ratio (Ancova model: adjustment for country and baseline titre pooled variance); LL = lower limit, UL = upper limit * Non-inferiority criterion: UL of the 2-sided 95% CIs on the rsba GMT ratios ( over ) < 2-fold for antibodies against all meningococcal serogroups. Primary Efficacy Variable(s): Vaccine response for rsba antibodies 1 month after vaccination, GSK rsba assay (ATP cohort for immunogenicity) Vaccine response 95% CI Antibody N n % LL UL rsba-mena * Control* rsba-menc * Control* rsba-menw-135 * Control* rsba-meny * Control* Vaccine response defined as: For initially seronegative subjects, antibody titre 1:32 For initially seropositive subjects: antibody titre 4 fold the pre-vaccination antibody titre n/% = number/percentage of responders 95% CI = exact 95% confidence interval, LL = Lower Limit, UL = Upper Limit *Primary outcome variable Primary Efficacy Variable(s): Percentage of subjects with rsba titres equal to or above the cut-off values of 1:8 and 1:128 and GMTs, GSK rsba assay (ATP cohort for immunogenicity) 1:8 1:128 GMT* 95% CI 95% CI 95% CI Antibody Timing N n % LL UL n % LL UL value LL UL rsba-mena PRE PI(M1)* PRE PI(M1)* Control PRE PI(M1) rsba-menc PRE PI(M1)* PRE PI(M1)* Control PRE PI(M1) rsba-menw- 135 PRE PI(M1)* PRE PI(M1)* Control PRE PI(M1) rsba-meny PRE PI(M1)* PRE PI(M1)*

5 Control PRE PI(M1) GMT = geometric mean antibody titre calculated on all subjects n/% = number/percentage of subjects with titre within the specified range 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit PRE = Pre-vaccination at Month 0 PI(M1) = Post-vaccination at Month 1 *Primary outcome variable Secondary Outcome Variable(s): Percentage of subjects with rsba titres equal to or above the cut-off values of 1:8 and 1:128 and GMTs, HPA rsba assay (ATP cohort for immunogenicity) 1:8 1:128 GMT 95% CI 95% CI 95% CI Antibody Timing N n % LL UL n % LL UL value LL UL rsba-mena PRE PI(M1) Control PRE PI(M1) rsba-menc PRE PI(M1) Control PRE PI(M1) rsba-menw-135 PRE PI(M1) Control PRE PI(M1) rsba-meny PRE PI(M1) Control PRE PI(M1) GMT = geometric mean antibody titre calculated on all subjects n/% = number/percentage of subjects with titre within the specified range 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit PRE = Pre-vaccination at Month 0 PI(M1) = Post-vaccination at Month 1 Secondary Outcome Variable(s): Vaccine response for rsba antibodies 1 month after vaccination, HPA rsba assay (ATP cohort for immunogenicity) Vaccine response 95% CI Antibody N n % LL UL rsba-mena Control rsba-menc Control rsba-menw Control rsba-meny Control Vaccine response defined as: For initially seronegative subjects, antibody titre 1:32 For initially seropositive subjects: antibody titre 4 fold the pre-vaccination antibody titre n/% = number/percentage of responders

6 95% CI = exact 95% confidence interval, LL = Lower Limit, UL = Upper Limit Secondary Outcome Variable(s): Percentage of subjects reporting solicited local symptoms during the 4-day (Days 0-3) post-vaccination period (Total Vaccinated cohort) Control 95 % CI 95 % CI 95 % CI Symptom Intensity N n % LL UL N n % LL UL N n % LL UL Pain Any Grade Redness Any >50 mm Swelling Any >50 mm N = number of subjects with the 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= occurrence of any local symptom regardless of intensity grade Grade 3 pain: pain that prevented normal activity Secondary Outcome Variable(s): Percentage of subjects reporting solicited general symptoms during the 4-day (Days 0-3) post-vaccination period (Total Vaccinated cohort) Control 95 % CI 95 % CI 95 % CI Symptom Intensity/ Relationship N n % LL UL N n % LL UL N n % LL UL Fatigue Any Grade Related Gastrointestinal Any Grade Related Headache Any Grade Related Temperature /(Orally) >37.5 C >39.5 C Related N = number of subjects with the 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= occurrence of any general symptom regardless of intensity grade or relationship to vaccination Grade 3: symptom that prevented normal activity Related: Symptom assessed by the investigator as related to study vaccine administration Secondary Outcome Variable(s): Percentage of subjects reporting NOCI(s) during the 31-day (Days 0-30) post-vaccination period (Total Vaccinated cohort) NOCIs Control Subjects with NOCI(s), n (%) 0 (0.0) 0 (0.0) 0 (0.0) Safety Results: Number (%) of subjects with unsolicited adverse events during the 31-day (Days 0-30) post-vaccination period (Total Vaccinated cohort) Most frequent adverse events - On-Therapy (occurring within Days 0-30 following vaccination) Control Subjects with any AE(s), n (%) 103 (26.4) 94 (24.1) 86 (22.1) Headache 17 (4.4) 12 (3.1) 13 (3.3) Nasopharyngitis 14 (3.6) 11 (2.8) 15 (3.8)

7 Dysmenorrhoea 14 (3.6) 14 (3.6) 6 (1.5) Upper respiratory tract infection 11 (2.8) 11 (2.8) 11 (2.8) Influenza 8 (2.1) 9 (2.3) 7 (1.8) Diarrhoea - 3 (0.8) 7 (1.8) Rhinitis allergic 4 (1.0) 3 (0.8) 3 (0.8) Pyrexia 4 (1.0) - 4 (1.0) Myalgia 4 (1.0) 3 (0.8) - Rhinitis - 6 (1.5) - Hypoaesthesia 3 (0.8) - 2 (0.5) Toothache 3 (0.8) - 2 (0.5) Nasal congestion - 3 (0.8) - Pharyngitis (0.8) Migraine (0.5) Pain in extremity (0.5) Somnolence (0.5) Vaginal infection (0.5) Vertigo (0.5) Counting rule applied: As there were more than 30 subjects per treatment group and 3 groups, only the 10 most frequent events in each treatment group are to be listed. -: Implies that the adverse event was not reported in the particular group or that the adverse event was reported in the particular group but did not fall within the pre-defined counting rule of 10 most frequent events for that group. Safety Results: Number (%) of subjects with serious adverse events during the 31-day (Days 0-30) post-vaccination period (Total Vaccinated cohort) Serious adverse event, n (%) [n considered by the investigator to be related to study medication] All SAEs Control Subjects with any SAE(s), n (%) [n assessed by the investigator 0 (0.0) [0] 1 (0.3) [1] 0 (0.0) [0] as related] Blighted ovum 0 (0.0) [0] 1 (0.3) [1] 0 (0.0) [0] Fatal SAEs Control Subjects with fatal SAE(s), n (%) [n assessed by the investigator as related] 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0] Conclusion: One month after vaccination, the percentages of responders in terms of rsba antibodies were at least 79.1% and 73.7% in the and Control groups, respectively, for the 4 meningococcal serogroups, as measured by GSK assay. At the same time point, the adjusted rsba GMTs were and for MenA, and for MenC, and for MenW-135 and and for Men-Y in the and groups, respectively, as measured by GSK assay. At least 1 AE were reported during the 31 day follow-up period after vaccination by 103 (26.4%) subjects, 94 (24.1%) subjects, and 86 (22.1%) subjects in, and Control groups, respectively. One non-fatal SAE was reported by a subject in during the 31-day follow-up period after vaccination; the SAE was assessed by the investigator as related to the study vaccination. No SAEs were reported in the and Control groups during the 31- day post-vaccination period. Date updated: 14-November-2013