14 CLINICAL STUDIES
The immunogenicity of Trumenba described in this section is based on results from four clinical studies:
- Following the two-dose schedule (0 and 6 months) in subjects 10 through 25 years of age in the U.S. and Europe (Study 1057);
- Following the three-dose schedule (0, 2, and 6 months) in subjects 10 through 25 years of age in the U.S., Canada, and Europe (Studies 1009 and 1016); and
- Following the two-dose (0 and 6 months) and three-dose schedules (0, 1–2, and 6 months) in subjects 11 through 18 years of age in Europe (Study 1012).
Serum bactericidal antibodies were measured with hSBA assays that used each of four meningococcal serogroup B strains. These four primary test strains express fHbp variants representing the two subfamilies (A and B) of meningococcal serogroup B strains causing invasive disease in the U.S. and Europe. The studies assessed the proportions of subjects with a 4-fold or greater increase in hSBA titer for each of the four primary strains. The studies also assessed the composite response to the four primary strains combined (proportion of subjects who achieved a hSBA titer greater than or equal to 1:8 [three strains] and 1:16 [one strain]). To assess the effectiveness of the two- and three-dose schedules of Trumenba against diverse meningococcal serogroup B strains, the proportion of subjects achieving a defined hSBA titer (≥LLOQ) following completion of the two- or three-dose series was evaluated against a panel of 10 additional strains, each expressing a different fHbp variant.
14.1 Immunogenicity
The hSBA responses to each of the primary strains observed after the second dose of Trumenba in Study 1057 are presented in Table 7.
| fHbp Variant‡ | N§ | % (95% CI)¶ | |
|---|---|---|---|
| Abbreviations: CI=confidence interval; fHbp=factor H binding protein; hSBA=serum bactericidal assay using human complement; LLOQ=lower limit of quantitation; LOD=limit of detection. Note: LLOQ = 1:16 for A22; 1:8 for A56, B24, and B44. Note: The 4-fold increase is defined as follows: (1) For subjects with a baseline hSBA titer <1:4, a response is defined as an hSBA titer ≥1:16. (2) For subjects with a baseline hSBA titer ≥ LOD and < LLOQ, a response is defined as an hSBA titer ≥4 times the LLOQ. (3) For subjects with a baseline hSBA titer ≥ LLOQ, a response is defined as an hSBA titer ≥4 times the baseline titer. Note: Pre-specified criteria for assessment of hSBA responses (4-fold rise in titer to each primary test strain, and titer above LLOQ for all four primary test strains) among subjects in the U.S. and Europe were met in this study for all test strains except strain A22. Pre-specified criteria for the lower bound of the 95% CI for 4-fold rise in titer were set at 75%, 85%, 55%, and 60%, respectively, for A22, A56, B24, and B44, and 65% for the composite hSBA response for all four primary test strains. | |||
| |||
| ≥4-Fold Increase | |||
| PMB80 (A22) | Dose 2 | 827 | 73.8 (70.6, 76.7) |
| PMB2001 (A56) | Dose 2 | 823 | 95.0 (93.3, 96.4) |
| PMB2948 (B24) | Dose 2 | 835 | 67.4 (64.1, 70.6) |
| PMB2707 (B44) | Dose 2 | 850 | 86.4 (83.9, 88.6) |
| Composite hSBA Response# | |||
| Before Dose 1 | 799 | 1.8 (1.0, 2.9) | |
| Dose 2 | 814 | 74.3 (71.2, 77.3) | |
The hSBA responses after the second dose of Trumenba in Study 1057 against a panel of 10 additional strains representing the diversity of meningococcal fHbp types prevalent among strains circulating in the US are presented in Table 8.
| fHbp Variant‡ | N§ | % (95% CI)¶ | |
|---|---|---|---|
| Abbreviations: CI=confidence interval; fHbp=factor H binding protein; hSBA=serum bactericidal assay using human complement; LLOQ=lower limit of quantitation. Note: LLOQ = 1:16 for A06, A12, and A19; 1:8 for A07, A15, A29, B03, B09, B15, and B16. | |||
| |||
| PMB3175 (A29) | Before Dose 1 | 166 | 4.8 (2.1, 9.3) |
| Dose 2 | 166 | 95.2 (90.7, 97.9) | |
| PMB3010 (A06) | Before Dose 1 | 157 | 5.7 (2.7, 10.6) |
| Dose 2 | 159 | 89.3 (83.4, 93.6) | |
| PMB3040 (A07) | Before Dose 1 | 150 | 32.0 (24.6, 40.1) |
| Dose 2 | 157 | 96.8 (92.7, 99.0) | |
| PMB824 (A12) | Before Dose 1 | 154 | 5.2 (2.3, 10.0) |
| Dose 2 | 157 | 83.4 (76.7, 88.9) | |
| PMB1672 (A15) | Before Dose 1 | 166 | 22.9 (16.7, 30.0) |
| Dose 2 | 165 | 89.1 (83.3, 93.4) | |
| PMB1989 (A19) | Before Dose 1 | 167 | 5.4 (2.5, 10.0) |
| Dose 2 | 167 | 90.4 (84.9, 94.4) | |
| PMB1256 (B03) | Before Dose 1 | 172 | 3.5 (1.3, 7.4) |
| Dose 2 | 164 | 74.4 (67.0, 80.9) | |
| PMB866 (B09) | Before Dose 1 | 171 | 9.9 (5.9, 15.4) |
| Dose 2 | 166 | 71.1 (63.6, 77.8) | |
| PMB431 (B15) | Before Dose 1 | 172 | 6.4 (3.2, 11.2) |
| Dose 2 | 167 | 85.0 (78.7, 90.1) | |
| PMB648 (B16) | Before Dose 1 | 172 | 8.1 (4.5, 13.3) |
| Dose 2 | 164 | 77.4 (70.3, 83.6) | |
The hSBA responses to each of the primary strains observed in U.S. subjects after the third dose of Trumenba are presented for Study 1009 and Study 1016 in Table 9.
| Study 1009 | Study 1016 | ||||
|---|---|---|---|---|---|
| (10 through 18 Years of Age) | (18 through 25 Years of Age) | ||||
| N¶ | % (95% CI)# | N¶ | % (95% CI)# | ||
| fHbp VariantÞ | |||||
| Abbreviations: CI=confidence interval; fHbp=factor H binding protein; hSBA=serum bactericidal assay using human complement; LLOQ=lower limit of quantitation; LOD=limit of detection. | |||||
| Note: LLOQ = 1:16 for A22; 1:8 for A56, B24, and B44. | |||||
| Note: The 4-fold increase is defined as follows: (1) For subjects with a baseline hSBA titer <1:4, a response is defined as an hSBA titer ≥1:16. (2) For subjects with a baseline hSBA titer ≥ LOD and < LLOQ, a response is defined as an hSBA titer ≥4 times the LLOQ. (3) For subjects with a baseline hSBA titer ≥ LLOQ, a response is defined as an hSBA titer ≥4 times the baseline titer. | |||||
| Note: Pre-specified criteria for assessment of hSBA responses (4-fold rise in titer to each primary test strain, and titer above LLOQ for all four primary test strains) among U.S. subjects were met in these studies. For Study 1009 pre-specified criteria for the lower bound of the 95% CI for 4-fold rise in titer were set at 75%, 85%, 65%, and 60%, respectively, for A22, A56, B24 and B44, and 75% for the composite hSBA response for all four primary test strains. For Study 1016 pre-specified criteria for the lower bound of the 95% CI for 4-fold rise in titer were set at 55%, 85%, 50%, and 60%, respectively, for A22, A56, B24, and B44, and 60% for the composite hSBA response for all four primary test strains. | |||||
| |||||
| ≥4-Fold Increase | |||||
| PMB80 (A22) | Dose 3 | 587 | 86.2 (83.1, 88.9) | 644 | 81.1 (77.8, 84.0) |
| PMB2001 (A56) | Dose 3 | 526 | 92.0 (89.4, 94.2) | 621 | 90.7 (88.1, 92.8) |
| PMB2948 (B24) | Dose 3 | 585 | 81.9 (78.5, 84.9) | 634 | 83.9 (80.8, 86.7) |
| PMB2707 (B44) | Dose 3 | 555 | 88.3 (85.3, 90.8) | 643 | 79.3 (76.0, 82.4) |
| Composite hSBA Responseß | |||||
| Before Dose 1 | 507 | 0.6 (0.1, 1.7) | 610 | 3.3 (2.0, 5.0) | |
| Dose 3 | 537 | 85.7 (82.4, 88.5) | 625 | 82.4 (79.2, 85.3) | |
The hSBA responses after the third dose of Trumenba against a panel of 10 additional strains representing the diversity of meningococcal fHbp types prevalent among strains circulating in the U.S. are presented for Study 1009, and Study 1016 in Table10.
| Study 1009 | Study 1016 | ||||
|---|---|---|---|---|---|
| (10 through 18 Years of Age) | (18 through 25 Years of Age) | ||||
| fHbp Variant‡ | N§ | % (95% CI)¶ | N§ | % (95% CI)¶ | |
| Abbreviations: CI=confidence interval; fHbp=factor H binding protein; hSBA=serum bactericidal assay using human complement; LLOQ=lower limit of quantitation. | |||||
| Note: LLOQ = 1:16 for A06, A12, and A19; 1:8 for A07, A15, A29, B03, B09, B15, and B16. | |||||
| |||||
| PMB3175 (A29) | Before Dose 1 | 169 | 11.2 (6.9, 17.0) | 160 | 23.8 (17.4, 31.1) |
| Dose 3 | 176 | 98.9 (96.0, 99.9) | 162 | 98.8 (95.6, 99.9) | |
| PMB3010 (A06) | Before Dose 1 | 178 | 7.9 (4.4, 12.8) | 166 | 10.8 (6.6, 16.6) |
| Dose 3 | 179 | 97.8 (94.4, 99.4) | 164 | 89.0 (83.2, 93.4) | |
| PMB3040 (A07) | Before Dose 1 | 170 | 37.6 (30.3, 45.4) | 165 | 55.8 (47.8, 63.5) |
| Dose 3 | 178 | 96.1 (92.1, 98.4) | 165 | 95.2 (90.7, 97.9) | |
| PMB824 (A12) | Before Dose 1 | 180 | 5.0 (2.3, 9.3) | 166 | 4.8 (2.1, 9.3) |
| Dose 3 | 180 | 76.1 (69.2, 82.1) | 165 | 66.7 (58.9, 73.8) | |
| PMB1672 (A15) | Before Dose 1 | 170 | 15.9 (10.7, 22.3) | 159 | 30.2 (23.2, 38.0) |
| Dose 3 | 166 | 86.7 (80.6, 91.5) | 159 | 89.9 (84.2, 94.1) | |
| PMB1989 (A19) | Before Dose 1 | 174 | 5.7 (2.8, 10.3) | 158 | 23.4 (17.1, 30.8) |
| Dose 3 | 173 | 91.9 (86.8, 95.5) | 163 | 94.5 (89.8, 97.4) | |
| PMB1256 (B03) | Before Dose 1 | 183 | 2.2 (0.6, 5.5) | 164 | 5.5 (2.5, 10.2) |
| Dose 3 | 181 | 92.3 (87.4, 95.7) | 161 | 84.5 (77.9, 89.7) | |
| PMB866 (B09) | Before Dose 1 | 180 | 12.2 (7.8, 17.9) | 165 | 13.9 (9.0, 20.2) |
| Dose 3 | 182 | 85.7 (79.8, 90.5) | 162 | 72.2 (64.7, 79.0) | |
| PMB431 (B15) | Before Dose 1 | 180 | 27.8 (21.4, 34.9) | 163 | 33.1 (26.0, 40.9) |
| Dose 3 | 183 | 97.3 (93.7, 99.1) | 163 | 95.7 (91.4, 98.3) | |
| PMB648 (B16) | Before Dose 1 | 180 | 6.7 (3.5, 11.4) | 161 | 11.8 (7.3, 17.8) |
| Dose 3 | 180 | 83.9 (77.7, 88.9) | 159 | 72.3 (64.7, 79.1) | |
In Study 1012, Trumenba was administered according to different schedules, including Group 1 (0, 1, and 6 months), Group 2 (0, 2, and 6 months) and Group 3 (0 and 6 months). The hSBA responses observed after the second dose in Groups 1, 2, and 3 and completion of the three-dose series in Group 1 and 2 are presented in Table 11.
| Group 1 | Group 2 | Group 3 | |
|---|---|---|---|
| 3-Dose Schedule (0, 1, and 6 Months)‡ | 3-Dose Schedule (0, 2, and 6 Months)§ | 2-Dose Schedule (0 and 6 Months)¶ | |
| fHbp Variant# | % (95% CI)Þ | % (95% CI)Þ | % (95% CI)Þ |
| Abbreviations: CI=confidence interval; fHbp=factor H binding protein; hSBA=serum bactericidal assay using human complement; LLOQ=lower limit of quantitation; NA=not applicable. | |||
| Note: LLOQ = 1:16 for PMB80 (A22) and 1:8 for PMB2001 (A56), PMB2948 (B24), and PMB2707 (B44). | |||
| Note: The ≥4-fold increase is defined as follows: (1) For subjects with a baseline hSBA titer <1:4, a ≥4-fold increase was defined as an hSBA titer ≥1:16. (2) For subjects with a baseline hSBA titer ≥ LOD and < LLOQ, a response is defined as an hSBA titer ≥4 times the LLOQ. (3) For subjects with a baseline hSBA titer ≥ LLOQ, a response is defined as an hSBA titer ≥4 times the baseline titer. | |||
| |||
| ≥4-Fold Increase | |||
| PMB80 (A22) | |||
| Dose 2 | 58.8 (51.4, 66.0) | 72.5 (66.4, 78.0) | 82.3 (76.3, 87.3) |
| Dose 3 | 77.6 (70.9, 83.4) | 87.7 (81.6, 92.3) | NA |
| PMB2001 (A56) | |||
| Dose 2 | 87.8 (82.2, 92.2) | 90.7 (86.2, 94.1) | 90.1 (85.1, 93.8) |
| Dose 3 | 91.2 (86.1, 94.9) | 93.8 (88.8, 97.0) | NA |
| PMB2948 (B24) | |||
| Dose 2 | 51.1 (43.6, 58.5) | 54.2 (47.7, 60.7) | 64.5 (57.4, 71.1) |
| Dose 3 | 74.1 (67.1, 80.2) | 78.3 (71.1, 84.4) | NA |
| PMB2707 (B44) | |||
| Dose 2 | 48.1 (40.7, 55.6) | 53.4 (46.8, 59.9) | 66.0 (58.9, 72.6) |
| Dose 3 | 80.9 (74.5, 86.2) | 78.6 (71.4, 84.7) | NA |
| Composite Responseß | |||
| Before Dose 1 | 4.6 (2.0, 8.8) | 2.2 (0.7, 5.0) | 1.5 (0.3, 4.4) |
| Dose 2 | 52.0 (44.3, 59.7) | 52.0 (45.3, 58.6) | 72.9 (65.9, 79.1) |
| Dose 3 | 80.3 (73.7, 85.9) | 81.8 (74.9, 87.4) | NA |
14.2 Concomitant Vaccine Administration
Study B1971011 (Study 1011) evaluated the immunogenicity of concomitantly administered Trumenba and Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant (HPV4) (Merck & Co, Inc.). U.S. subjects 11 through 17 years of age were randomized into three groups: Group 1 received Trumenba and HPV4 (N=992), Group 2 received Trumenba and saline (N=990), and Group 3 received saline and HPV4 (N=501). All vaccines were administered according to a 0-, 2- and 6-month schedule. Immune responses were evaluated by comparisons of geometric mean titer [GMT] for each HPV type at 1 month after the third HPV4 vaccination (Group 1 vs. Group 3), and hSBA GMTs using two meningococcal serogroup B strains [variants A22 and B24] 1 month after the third Trumenba vaccination (Group 1 vs. Group 2). The noninferiority criteria for the comparisons of GMTs [lower limit of the 2-sided 95% confidence interval (CI) of the GMT ratio (Group 1/Group 3 for HPV and Group 1/Group 2 for meningococcal serogroup B strains) >0.67] were met for three HPV types (6, 11 and 16) and for the meningococcal serogroup B strains tested. For HPV-18, the lower bound of the 95% CI for the GMT ratio was 0.62 at 1 month after the third HPV4 vaccination
Study B1971015 (Study 1015) evaluated the immunogenicity of concomitantly administered Trumenba and Meningococcal (Serogroups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine (MenACWY) (Sanofi Pasteur Inc.) and Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap) (Sanofi Pasteur Ltd.) vaccines. U.S. subjects 10 through 12 years of age were randomized into three groups: Group 1 received Trumenba at 0, 2, and 6 months, and MenACWY and Tdap were coadministered with the first Trumenba dose (N=883). Group 2 received saline at 0, 2 and 6 months, and MenACWY and Tdap were coadministered with the first saline injection (N=870). Group 3 received Trumenba at 0, 2 and 6 months, and saline was coadministered with the first Trumenba dose (N=875). Immune responses were evaluated by comparisons of GMTs for each of the MenACWY and Tdap antigens 1 month after the first Trumenba vaccination, and hSBA GMTs using two meningococcal serogroup B strains [variants A22 and B24] 1 month after the third Trumenba vaccination. The noninferiority criteria for the comparisons of GMTs [lower limit of the 2-sided 95% CI of the GMT ratio (Group 1/Group 3 for meningococcal serogroup B strains and Group 1/Group 2 for MenACWY and Tdap) >0.67] were met for all antigens.