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

Transcription

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.: (-043 EXT: 036 Y2, 3, 4, 5) Title: Persistence of antibodies after vaccination with GSK Biologicals meningococcal vaccine GSK in adolescents and young adults Nimenrix - GSK (): GlaxoSmithKline (GSK) Biologicals meningococcal serogroups A, C, W- and Y tetanus toxoid conjugate vaccine. Rationale: The aim of this study was to evaluate the persistence of the immune response of vaccine up to 5 years after vaccination as compared to Mencevax AC vaccine when the vaccines were given in healthy adolescents aged 11 to 17 years in study (-036). Mencevax AC (): GSK Biologicals meningococcal serogroups A, C, W-, Y polysaccharide vaccine Note: This summary presents results up to Year 4 (Month 48) only. It will be updated when results at later time points become available. For results on the primary study, please refer to the CTRS of the -036 (109069) study. Phase: III Study Period: 8 September 2009 to - 01 May 2010 (Month 24) - 18 April 2011 (Month 36) - 02 April 2012 (Month 48) Study Design: Open, multi-centre study with 2 parallel groups. The subjects were randomised in a 3:1 ratio in study The subjects were allocated to the same group as in the primary vaccination study. Centres: 4 centres in India and 1 centre in the Philippines Indication: Immunization of healthy male and female adolescents and young adults, aged between 11 and 17 years at the time of primary vaccination, against meningococcal serogroup A, C, W- and Y diseases. Treatment: The study groups in the primary study were as follows; Group: Subjects vaccinated with a single dose of vaccine Group: Subjects vaccinated with a single dose of vaccine No vaccine was administered during this long-term persistence study. Objectives: Immunogenicity At 24, 36, 48, and 60* months after primary vaccination of adolescents with or vaccine, To evaluate the persistence of meningococcal antibodies in terms of percentage of subjects with serum bactericidal antibodies using baby rabbit complement (rsba) titres 1:8 for each of the 4 serogroups. *Results of the Month 60 time point were not available at the time of writing this summary. The CTRS will be updated when they become available. Primary Outcome/Efficacy Variable: Immunogenicity Persistence of immunogenicity with respect to components of the investigational vaccine, 24, 36, 48 and 60* months post primary dose: rsba meningococcal serogroup A (MenA) titres 1:8. rsba meningococcal serogroup C (MenC) titres 1:8. rsba meningococcal serogroup W- (MenW-) titres 1:8. rsba meningococcal serogroup Y (MenY) titres 1:8. * Results of the Month 60 time point were not available at the time of writing this summary. The CTRS will be updated when they become available. Secondary Outcome/Efficacy Variable(s): Immunogenicity Persistence of immunogenicity with respect to components of the investigational vaccine, 24, 36, 48 and 60* months post primary dose (on secondary readouts): MenA titres 1:128 and titres MenC titres 1:128 and titres MenW- titres 1:128 and titres MenY titres 1:128 and titres Persistence of immunogenicity with respect to components of the investigational vaccine 24 months post primary dose (on

2 secondary readouts): polysaccharide A (anti-psa) concentrations 0.3 g/ml, 2.0 g/ml and concentrations (Enzyme-linked immunosorbent assay [ELISA]). polysaccharide C (anti-psc) concentrations 0.3 g/ml, 2.0 g/ml and concentrations (ELISA). polysaccharide W- (anti-psw-) concentrations 0.3 g/ml, 2.0 g/ml and concentrations (ELISA). polysaccharide Y (anti-psy) concentrations 0.3 g/ml, 2.0 g/ml and concentrations (ELISA). * Results of the Month 60 time point were not available at the time of writing this summary. The CTRS will be updated when they become available. Statistical Methods: The analyses were performed on the Total cohort at Month X (24, 36 and 48) and the According-to-Protocol (ATP) cohort for persistence at Month X (24, 36 and 48): The Total cohort at Month X (24, 36 and 48) included all subjects who received their complete vaccination course in study [-036] and who came back for the Month X (24, 36 and 48) time point. The ATP cohort for persistence at Month X (24, 36 and 48) included all evaluable subjects (i.e. who received their complete vaccination course in study [-036] according to their treatment group assignment, those meeting all eligibility criteria, complying with the procedures and intervals defined in the protocol) for whom assay results were available for at least one tested antigen at the Month X (24, 36 and 48), who had not received a meningococcal polysaccharide or a meningococcal polysaccharide conjugate vaccine not planned in protocol [-036] between the start of study [-036] and the Month X (24, 36 and 48), who did not have a history of meningococcal serogroup A, C, W-, and Y disease prior to the Month X (24, 36 and 48), who complied with the blood sampling intervals defined in the protocol for the Month X (24, 36 and 48), who did not have an immunocompromising medical condition, who had not received any immunosuppressant(s) or other immune modifying drug(s), immunoglobulins, any blood products, investigational drugs, and/or investigational vaccines. Analysis of persistence The analysis of persistence was performed on the ATP cohort for persistence at Month X (24, 36 and 48) and on the Total cohort at Month 24. At Months 24, 36 and 48, geometric mean titers (GMTs) and percentages of subjects with titers above proposed cut-offs were tabulated with 95% confidence intervals (CIs) for MenA, MenC, MenW-, MenY for both groups.. rsba data were tested at GSK Biologicals laboratory until the Month 24 time point and at Public Health England (PHE) laboratory at Months 36 and 48. At Month 24, geometric mean concentrations (GMCs) and percentages of subjects with concentrations above proposed cutoffs were tabulated with 95% CIs for anti-psa, anti-psc, anti-psw- and anti-psy for both groups. A randomized subset of half of the subjects had sera tested for anti-psa and anti-psc by ELISA while the other half were tested for anti PSW- and anti-psy by ELISA. Analysis of safety The analysis of safety was performed on the Total cohort at Month X (24, 36 and 48). The number and percentage of subjects who experienced serious adverse events (SAEs) that were related to study participation or were related to a concurrent GSK medication were tabulated according to the Medical Dictionary for Regulatory Activities (MedDRA) preferred terms from the last visit of the primary vaccination study up to Month 48. Study Population: Healthy males and females who had been vaccinated with a meningococcal vaccine in the primary study (-036), who had no history of meningococcal disease and who had no administration of a meningococcal polysaccharide or a meningococcal polysaccharide conjugate vaccine since the previous vaccination in study (-036). Written informed consent was obtained from the parent(s)/guardian(s) and informed assent from the subject if he/she was less than 18 years of age. Written informed consent was obtained from the subject if he/she had achieved his/her 18 th birthday since the primary vaccination study. Month 24 Number of subjects Group Group Planned*, N Entered, N (Total cohort at Month 24) Completed at Month 24, n (%) 521 (100) 168 (100) Total Number Subjects Withdrawn, n (%) 0 (0.0) 0 (0.0) Withdrawn due to Adverse Events, n (%) 0 (0.0) 0 (0.0) Withdrawn due to Lack of Efficacy, n (%) Not applicable Not applicable Withdrawn for other reasons, n (%) 0 (0.0) 0 (0.0)

3 Demographics Group Group N (Total cohort at Month 24) Females:Males 273:248 86:82 Mean Age, years (SD) 16.4 (1.94) 16.4 (2.00) Asian - South East Asian heritage, n (%) 293 (56.2) 97 (57.7) Month 36 Number of subjects Group Group Planned*, N Entered, N (Total cohort at Month 36) Completed at Month 36, n (%) 488 (100) 155 (100) Total Number Subjects Withdrawn, n (%) 0 (0.0) 0 (0.0) Withdrawn due to Adverse Events, n (%) 0 (0.0) 0 (0.0) Withdrawn due to Lack of Efficacy, n (%) Not applicable Not applicable Withdrawn for other reasons, n (%) 0 (0.0) 0 (0.0) Demographics Group Group N (Total cohort at Month 36) Females:Males 256:232 80:75 Mean Age, years (SD) 17.3 (1.96) 17.3 (1.98) Asian - South East Asian heritage, n (%) 294 (60.2) 97 (62.6) Month 48 Number of subjects Group Group Planned*, N Entered, N (Total cohort at Month 48) Completed at Month 48, n (%) 407 (100) 134 (100) Total Number Subjects Withdrawn, n (%) 0 (0.0) 0 (0.0) Withdrawn due to Adverse Events, n (%) 0 (0.0) 0 (0.0) Withdrawn due to Lack of Efficacy, n (%) Not applicable Not applicable Withdrawn for other reasons, n (%) 0 (0.0) 0 (0.0) Demographics Group Group N (Total cohort at Month 48) Females:Males 212:195 68:66 Mean Age, years (SD) 18.1 (2.01) 18.1 (1.96) Asian - South East Asian heritage, n (%) 293 (72.0) 97 (72.4) *Assuming drop-out rate of 20% each year since the end of the primary study. Primary Efficacy Results: Percentage of subjects with rsba titres equal to or above the cut-off values of 1:8 and 1:128 and GMTs (ATP cohort for persistence at Month 24) GSK Biologicals laboratory assay Antibody Group Timing N 1:8* 1:128 GMT n % 95% CI n % 95% CI Value 95% CI LL UL LL UL LL UL MenA MenC MenW- PRE PI(M1) PI(M24)* PRE PI(M1) PI(M24)* PRE PI(M1) PI(M24)* PRE PI(M1) PI(M24)* PRE PI(M1) PI(M24)*

4 MenY PRE PI(M1) PI(M24)* PRE PI(M1) PI(M24)* PRE PI(M1) PI(M24)* GMT = geometric mean antibody titre calculated on all subjects n/% = number/percentage of subjects with titre within the specified range * Primary outcome variable Titres were expressed as the reciprocal of the dilution resulting in 50% inhibition Primary Efficacy Results: Percentage of subjects with rsba titres equal to or above the cut-off values of 1:8 and 1:128 and GMTs (Total cohort at Month 24) Antibody Group Timing N 1:8* 1:128 GMT n % 95% CI n % 95% CI Value 95% CI LL UL LL UL LL UL MenA MenC MenW- MenY PRE PI(M1) PI(M24)* PRE PI(M1) PI(M24)* PRE PI(M1) PI(M24)* PRE PI(M1) PI(M24)* PRE PI(M1) PI(M24)* PRE PI(M1) PI(M24)* PRE PI(M1) PI(M24)* PRE PI(M1) PI(M24)* GMT = geometric mean antibody titre calculated on all subjects n/% = number/percentage of subjects with titre within the specified range

5 * Primary outcome variable Titres were expressed as the reciprocal of the dilution resulting in 50% inhibition Subjects with improper consent were excluded from the Total cohort at Month 24 Primary Efficacy Results: Percentage of subjects with rsba titres equal to or above the cut-off values of 1:8 and 1:128 and GMTs (ATP cohort for persistence at Month 36) - PHE laboratory assay Antibod Group Timing N n % LL UL n % LL UL Value LL UL y MenA MenC MenW- MenY PRE P1(M1) PI(M24) PI(M36)* PRE P1(M1) PI(M24) PI(M36)* PRE P1(M1) PI(M24) PI(M36)* PRE P1(M1) PI(M24) PI(M36)* PRE P1(M1) PI(M24) PI(M36)* PRE P1(M1) PI(M24) PI(M36)* PRE P1(M1) PI(M24) PI(M36)* PRE P1(M1) PI(M24) PI(M36)* GMT = geometric mean antibody titre calculated on all subjects n/% = number/percentage of subjects with titre within the specified range PI(M36) = Post-primary vaccination at Month 36 * Primary outcome variable Titres were expressed as the reciprocal of the dilution resulting in 50% inhibition Primary Efficacy Results: Percentage of subjects with rsba titres equal to or above the cut-off values of 1:8 and 1:128 and

6 GMTs (ATP cohort for persistence at Month 48) - PHE laboratory assay Antibod Group Timing N n % LL UL n % LL UL Value LL UL y PRE MenA P1(M1) PI(M24) PI(M36) MenC MenW- MenY PI(M48)* PRE P1(M1) PI(M24) PI(M36) PI(M48)* PRE P1(M1) PI(M24) PI(M36) PI(M48)* PRE P1(M1) PI(M24) PI(M36) PI(M48)* PRE P1(M1) PI(M24) PI(M36) PI(M48)* PRE P1(M1) PI(M24) PI(M36) PI(M48)* PRE P1(M1) PI(M24) PI(M36) PI(M48)* PRE P1(M1) PI(M24) PI(M36) PI(M48)* GMT = geometric mean antibody titre calculated on all subjects n/% = number/percentage of subjects with titre within the specified range PI(M36) = Post-primary vaccination at Month 36 PI(M48) = Post-primary vaccination at Month 48 * Primary outcome variable Titres were expressed as the reciprocal of the dilution resulting in 50% inhibition

7 Secondary Outcome Variables: Percentage of subjects with anti-ps concentrations equal to or above the cut-off values of 0.3 µg/ml and 2.0 µg/ml and GMCs (ATP cohort for persistence at Month 24) 0.3 μg/ml 2.0 μg/ml GMC (μg/ml) 95% CI 95% CI Value 95% CI Antibod Group Timing N n % LL UL n % LL UL LL UL y PSA PSC PSW- PSY PRE PI(M1) PI(M24) PRE PI(M1) PI(M24) PRE PI(M1) PI(M24) PRE PI(M1) PI(M24) PRE PI(M1) PI(M24) PRE PI(M1) PI(M24) PRE PI(M1) PI(M24) PRE PI(M1) PI(M24) GMC = geometric mean antibody concentration calculated on all subjects n/% = number/percentage of subjects with concentration within the specified range Secondary Outcome Variables: Percentage of subjects with anti-ps concentrations equal to or above the cut-off values of 0.3 µg/ml and 2.0 µg/ml and GMCs (Total cohort at Month 24) Antibod y PSA Group Timing N 0.3 μg/ml 2.0 μg/ml GMC (μg/ml) n % 95% CI n % 95% CI Value 95% CI LL UL LL UL LL UL PRE PI(M1) PI(M24) PRE PI(M1) PI(M24) PRE

8 PSC PI(M1) PI(M24) PRE PI(M1) PI(M24) PSW- PSY PRE PI(M1) PI(M24) PRE PI(M1) PI(M24) PRE PI(M1) PI(M24) PRE PI(M1) PI(M24) GMC = geometric mean antibody concentration calculated on all subjects n/% = number/percentage of subjects with concentration within the specified range Subjects with improper consent were excluded from the Total cohort at Month 24 Safety Results: Number (%) of subjects with unsolicited AEs. No information about unsolicited AEs was collected during this study as no product was administered. Safety Results: Number (%) of subjects with vaccine or study procedure-related SAE(s) up to Month 24 (Total cohort at Month 24) Serious adverse event, n (%) [n considered by the investigator to be related to study medication] All SAEs Subjects with any SAE(s), n (%) [n assessed by the investigator as Fatal SAEs Group Group N = 521 N = 168 Group Group N = 521 N = 168 Subjects with fatal SAE(s), n (%) [n assessed by the investigator as Safety Results: Number (%) of subjects with vaccine or study procedure-related SAE(s) up to Month 36 (Total cohort at Month 36) Serious adverse event, n (%) [n considered by the investigator to be related to study medication] All SAEs Subjects with any SAE(s), n (%) [n assessed by the investigator as Fatal SAEs Group Group N = 488 N = 155 Group Group N = 488 N = 155 Subjects with fatal SAE(s), n (%) [n assessed by the investigator as Safety Results: Number (%) of subjects with vaccine or study procedure-related SAE(s) up to Month 48 (Total cohort at Month 48 ) Serious adverse event, n (%) [n considered by the investigator to be related to study medication] All SAEs Group Group

9 Subjects with any SAE(s), n (%) [n assessed by the investigator as Fatal SAEs Subjects with fatal SAE(s), n (%) [n assessed by the investigator as N = 407 N = 134 Group Group N = 407 N = 134 Conclusion: At 24 months after the administration of the primary vaccination, at least 99.2% of subjects in the Group and at least 94.7% of subjects in the Group had rsba titers 1:8 for each serogroup At 36 months after the administration of the primary vaccination, at least 82.0% of subjects in the Group and 30.0% of subjects in the Group had rsba titers 1:8 for each serogroup At 48 months after the administration of the primary vaccination, at least 77.2% of subjects in the Group and 26.9% of subjects in the Group had rsba titers 1:8 for each serogroup. No vaccine or study procedure-related SAEs were reported until Month 48. For safety results on the primary study, please refer to CTRS. Date updated: 10-June-2015