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.: 104020 (MeMuRu-OKA-043) Title: A phase III, partially blind, randomized, primary vaccination study to assess the immunogenicity and safety of three different lots of GlaxoSmithKline (GSK) Biologicals live attenuated measles-mumps-rubella-varicella vaccine (MeMuRu- OKA), when given as a two-dose schedule to healthy children in their second year of life. MeMuRu-OKA: GSK Biologicals' combined measles, mumps, rubella and varicella vaccine. Rationale: The aim of the study was to evaluate in a clinical setting the use of lots stored at +2C to +8C for several months, which mumps titres had decreased to s close to the proposed minimum or end of shelf life titres ( aged lots). GSK Biologicals Priorix and Varilrix were used as benchmarks. MMR (Priorix): GSK Biologicals' measles-mumps-rubella vaccine, V (Varilrix): GSK Biologicals' varicella vaccine. Phase: III Study Period: 11 May 2005 to 21 November 2005 Study Design: Partially blind*, randomized, controlled study with 4 parallel groups (2:2:2:1 ratio). *The study was carried out in a double-blind manner with respect to the 3 MeMuRu-OKA lots, open with respect to s MeMuRu-OKA lots A-B-C versus MMR_V. Centers: 51 centers in 4 countries: Finland, Germany, Greece and Poland. Indication: Active immunization of healthy children during their second year of life against measles, mumps, rubella and varicella diseases. Treatment: The 4 treatment groups were as follows: received 2 doses of MeMuRu OKA vaccine lot A ( fresh lot stored at -25C after release): one at Day 0 and one at Week 6, received 2 doses of MeMuRu OKA vaccine lot A ( aged lot stored at +2C to +8C after release): one at Day 0 and one at Week 6, received 2 doses of MeMuRu OKA vaccine lot B ( aged lot stored at +2C to+8c after release): one at Day 0 and one at Week 6, MMR_V received a first dose of MMR administered concomitantly with one dose of V at Day 0 and a second dose of MMR at Week 6. All vaccines were administered subcutaneously in the deltoid region of the arm, MMR-OKA & MMR in the left arm, V in the right arm. Objectives: To establish an observed seroconversion rate for mumps of at least 90% for each lot after the first dose by neutralization assay. Primary Outcome/Efficacy Variable: Mumps seroconversion rate after the first dose by neutralization assay defined as the percentage of subjects with anti-mumps titers 28 Estimated Dose50 (ED50). Secondary Outcome/Efficacy Variable(s): Immunogenicity Mumps seroconversion rate after the first dose by ELISA, defined as the percentage of subjects with anti-mumps titers 231 U/mL Seroconversion rates after the first dose defined as the percentage of subjects with: - Anti-measles titers 150 miu/ml, - Anti-rubella titers 4 IU/mL, - Anti-varicella titers 1: 4. Measles, mumps*, rubella and varicella seroconversion rates after the second dose. Measles, mumps, rubella and varicella Geometric Mean Titers (GMTs) after each dose. * Mumps seroconversion rate by neutralization assay and ELISA. Safety Occurrence of any and Grade 3 solicited local symptoms (injection site's redness, pain and swelling) within 4 days (Day 0-3) after each vaccination. Occurrence of any, Grade 3 and vaccine-related solicited general symptoms within 43 days (Day 0-42) after each
vaccination in terms of fever, rash, any sign of meningism including febrile convulsion and parotitis. Occurrence of any, Grade 3 and vaccine-related unsolicited adverse events (AEs) within 43 days (Day 0-42) after each vaccination. Occurrence of serious adverse events (SAEs) throughout the entire study period (Day 0 to Week 12). Statistical Methods: The analyses were performed on the Total Vaccinated Cohort and the According-To-Protocol (ATP) Cohort for immunogenicity. The Total Vaccinated Cohort included all vaccinated subjects with at least one vaccine administration documented. The ATP Cohort for immunogenicity included all subjects who received at least one dose of study /comparator vaccine, for whom administration site of study vaccine/comparator was correct, who did not receive a vaccine not specified or forbidden in the protocol, with pre-vaccination and with post serology data available for at least one of the vaccine antigens, who were seronegative to at least one vaccine antigen at baseline and who complied with protocol procedures. Analysis of immunogenicity The analysis was performed on the ATP Cohort for immunogenicity. For each treatment group, at each blood sampling time point, seroconversion rates with exact 95% confidence intervals (CIs) and GMTs with s were calculated for each antigen after each dose by pre vaccination serological status (seropositive/seronegative). Subjects without a pre vaccination result were not included in the analysis. Analysis of safety The analysis was performed on the Total Vaccinated Cohort. The number and percentage of subjects (with exact s) with each local solicited symptom (any and Grade 3) during the 4-day (Day 0-3) follow-up period after each vaccination were tabulated for each group. The number and percentage of subjects with each general solicited symptom (any, Grade 3 and related) during the 43-day (Day 0-42) follow-up period after each vaccination were tabulated for each group. The number and percentage of subjects with unsolicited AEs (any, Grade 3 and related) during the 43-day (Day 0-42) follow-up period after each vaccination were tabulated per group according to the Medical Dictionary for Regulatory Activities (MedDRA) preferred terms. The occurrence of SAEs during the entire study period was tabulated per group according to the MedDRA preferred terms. Study Population: Healthy male or female children between 11 and 21 months of age at the time of first vaccination, free of obvious health problems as established by medical history and clinical examination before entering into the study and with no history of measles, mumps, rubella and/or varicella vaccination and/or disease. Written informed consent was obtained from parent(s)/guardian(s) of each subject prior to study entry. Number of Subjects: MMR_V Planned, N 412 412 412 206 Randomized, N (Total Vaccinated Cohort) 407 408 410 213 Completed, n (%) 397 (97.5) 396 (97.1) 397 (96.8) 204 (95.8) Total Number Subjects Withdrawn, n (%) 10 (2.5) 12 (2.9) 13 (3.2) 9 (4.2) Withdrawn due to Adverse Events, n (%) 1 (0.2) 1 (0.2) 3 (0.7) 2 (0.9) Withdrawn due to Lack of Efficacy, n (%) Not applicable Not applicable Not applicable Not applicable Withdrawn for other reasons, n (%) 9 (2.2) 11 (2.7) 10 (2.4) 7 (3.3) Demographics MMR_V N (Total Vaccinated Cohort) 407 408 410 213 Females: Males 198:209 183:225 201:209 105:108 Mean Age, months (SD) 14.0 (2.27) 14.1 (2.37) 13.9 (2.17) 14.3 (2.40) White/Caucasian, n (%) 401 (98.5) 405 (99.3) 407 (99.3) 208 (97.7) Primary Efficacy Results: Seroconversion rates and GMTs for anti-mumps antibodies (neutralization assay) for initially seronegative subjects (ATP Cohort for immunogenicity) 28 ED50* GMT PI(D42)* 327 318 97.2 94.8 98.7 161.9 141.6 185.1 PII(D84) 319 318 99.7 98.3 100 489.6 442.0 542.2 PI(D42)* 337 321 95.3 92.4 97.3 154.7 135.0 177.2 PII(D84) 331 329 99.4 97.8 99.9 528.6 473.8 589.6 PI(D42)* 321 298 92.8 89.4 95.4 135.0 117.2 155.4 PII(D84) 320 319 99.7 98.3 100 518.6 465.6 577.7
MMR_V PI(D42)* 166 165 99.4 96.7 100 146.7 121.8 176.7 PII(D84) 164 163 99.4 96.6 100 429.6 373.5 494.1 n(%) = number(percentage) of subjects with titer specified cut-off = 95% confidence interval; LL = Lower Limit, UL = Upper Limit *Primary Outcome/Efficacy variable Seroconversion rates and GMTs for anti-mumps antibodies (ELISA) for initially seronegative subjects (ATP Cohort for immunogenicity) 231 U/mL GMT (U/mL) PI(D42) 378 345 91.3 88.0 93.9 924.2 837.4 1020.0 PII(D84) 379 373 98.4 96.6 99.4 1418.8 1317.4 1527.9 PI(D42) 360 320 88.9 85.2 91.9 925.1 830.6 1030.3 PII(D84) 366 363 99.2 97.6 99.8 1556.3 1442.7 1678.9 PI(D42) 371 327 88.1 84.4 91.2 902.1 808.7 1006.2 PII(D84) 376 367 97.6 95.5 98.9 1489.8 1375.3 1613.8 MMR_V PI(D42) 182 173 95.1 90.8 97.7 951.9 846.0 1071.1 PII(D84) 185 184 99.5 97.0 100 1432.8 1302.0 1576.8 n(%) = number(percentage) of subjects with titer specified cut-off = 95% confidence interval; LL = Lower Limit, UL = Upper Limit Seroconversion rates and GMTs for anti-measles antibodies for initially seronegative subjects (ATP Cohort for immunogenicity) 150 miu/ml GMT (miu/ml) PI(D42) 387 377 97.4 95.3 98.8 3549.1 3247.7 3878.4 PII(D84) 380 379 99.7 98.5 100 5524.5 5127.6 5952.2 PI(D42) 372 361 97.0 94.8 98.5 3531.7 3213.0 3882.0 PII(D84) 365 362 99.2 97.6 99.8 5509.3 5062.5 5995.6 PI(D42) 384 376 97.9 95.9 99.1 3389.0 3102.4 3702.0 PII(D84) 380 377 99.2 97.7 99.8 5222.5 4815.0 5664.4 MMR_V PI(D42) 190 181 95.3 91.2 97.8 1732.8 1488.9 2016.8 PII(D84) 188 185 98.4 95.4 99.7 2671.3 2310.6 3088.2 n(%) = number(percentage) of subjects with titer specified cut-off = 95% confidence interval; LL = Lower Limit, UL = Upper Limit Seropositivity rates and GMTs for anti-rubella antibodies for initially seronegative subjects (ATP Cohort for immunogenicity) 4 IU/mL GMT (IU/mL) PI(D42) 389 389 100 99.1 100 63.1 58.6 68.0 PII(D84) 382 382 100 99.0 100 119.7 112.8 127.0 PI(D42) 376 376 100 99.0 100 65.8 60.6 71.4 PII(D84) 369 369 100 99.0 100 121.2 113.4 129.6
PI(D42) 384 383 99.7 98.6 100 59.7 54.9 65.0 PII(D84) 380 380 100 99.0 100 125.0 117.7 132.8 MMR_V PI(D42) 189 189 100 98.1 100 82.4 73.9 91.9 PII(D84) 187 187 100 98.0 100 139.9 128.7 152.1 n(%) = number(percentage) of subjects with titer specified cut-off = 95% confidence interval; LL = Lower Limit, UL = Upper Limit Seropositivity rates and GMTs for anti-varicella antibodies for initially seronegative subjects (ATP Cohort for immunogenicity) 1:4 GMT PI(D42) 374 370 98.9 97.3 99.7 126.6 113.5 141.2 PII(D84) 367 366 99.7 98.5 100 2988.0 2690.9 3317.9 PI(D42) 358 348 97.2 94.9 98.7 83.6 73.7 94.9 PII(D84) 351 351 100 99.0 100 2792.4 2512.6 3103.3 PI(D42) 373 361 96.8 94.4 98.3 79.2 69.9 89.8 PII(D84) 371 371 100 99.0 100 2505.9 2251.8 2788.6 MMR_V PI(D42) 184 176 95.7 91.6 98.1 73.6 61.0 88.8 PII(D84) 182 177 97.3 93.7 99.1 85.8 70.0 105.2 n(%) = number(percentage) of subjects with titer specified cut-off = 95% confidence interval; LL = Lower Limit, UL = Upper Limit Incidence of solicited local symptoms reported during the 4-day (Day 0-3) post-vaccination period following each dose (Total Vaccinated Cohort) Symptom Intensity N=407 N=408 Pain Any 46 11.3 8.4 14.8 34 8.3 5.8 11.5 Grade 3 1 0.2 0.0 1.4 1 0.2 0.0 1.4 Redness Any 95 23.3 19.3 27.8 96 23.5 19.5 28.0 > 20 mm 0 0.0 0.0 0.9 1 0.2 0.0 1.4 Swelling Any 31 7.6 5.2 10.6 32 7.8 5.4 10.9 > 20 mm 0 0.0 0.0 0.9 1 0.2 0.0 1.4 N=401 N=404 Pain Any 42 10.5 7.7 13.9 38 9.4 6.7 12.7 Redness Any 117 29.2 24.8 33.9 115 28.5 24.1 33.1 > 20 mm 16 4.0 2.3 6.4 10 2.5 1.2 4.5 Swelling Any 44 11.0 8.1 14.4 44 10.9 8.0 14.3 > 20 mm 2 0.5 0.1 1.8 3 0.7 0.2 2.2 MMR _V N=410 N=213 Pain Any 40 9.8 7.1 13.0 21 9.9 6.2 14.7 Grade 3 0 0.0 0.0 0.9 0 0.0 0.0 1.7
Redness Any 99 24.1 20.1 28.6 50 23.5 18.0 29.7 > 20 mm 1 0.2 0.0 1.4 0 0.0 0.0 1.7 Swelling Any 31 7.6 5.2 10.6 14 6.6 3.6 10.8 > 20 mm 0 0.0 0.0 0.9 0 0.0 0.0 1.7 N=400 N=207 Pain Any 40 10.0 7.2 13.4 5 2.4 0.8 5.5 Grade 3 0 0.0 0.0 0.9 0 0.0 0.0 1.8 Redness Any 128 32.0 27.5 36.8 26 12.6 8.4 17.9 > 20 mm 15 3.8 2.1 6.1 1 0.5 0.0 2.7 Swelling Any 53 13.3 10.1 17.0 5 2.4 0.8 5.5 > 20 mm 5 1.3 0.4 2.9 0 0.0 0.0 1.8 N= number of subjects with an administered dose n(%)= number(percentage) of subjects for whom the symptom was reported at least once 95%CI= Exact 95% confidence interval; LL = lower limit, UL = upper limit Any= any solicited local symptom irrespective of intensity grade Grade 3 pain = Cried when limb was moved/spontaneously painful Incidence of solicited general symptoms reported during the 43-day (Day 0-42) post-vaccination period following each dose (Total Vaccinated Cohort) Symptom Intensity/ relationship N=407 N=408 38.0C 273 67.1 62.3 71.6 269 65.9 61.1 70.5 > 39.5C 64 15.7 12.3 19.6 53 13.0 9.9 16.6 Related 185 45.5 40.5 50.4 168 41.2 36.4 46.1 Rash Any 77 18.9 15.2 23.1 87 21.3 17.4 25.6 Grade 3 12 2.9 1.5 5.1 11 2.7 1.4 4.8 Related 27 6.6 4.4 9.5 40 9.8 7.1 13.1 Meningism N=401 N=404 38.0C 149 37.2 32.4 42.1 154 38.1 33.4 43.1 > 39.5C 32 8.0 5.5 11.1 31 7.7 5.3 10.7 Related 64 16.0 12.5 19.9 58 14.4 11.1 18.2 Rash Any 45 11.2 8.3 14.7 47 11.6 8.7 15.2 Grade 3 4 1.0 0.3 2.5 5 1.2 0.4 2.9 Related 9 2.2 1.0 4.2 6 1.5 0.5 3.2 Meningism Any 0 0.0 0.0 0.9 1 0.2 0.0 1.4
MMR_V N=410 N=213 38.0C 273 66.6 61.8 71.1 103 48.4 41.5 55.3 > 39.5C 69 16.8 13.3 20.8 14 6.6 3.6 10.8 Related 175 42.7 37.8 47.6 53 24.9 19.2 31.2 Rash Any 88 21.5 17.6 25.8 42 19.7 14.6 25.7 Grade 3 7 1.7 0.7 3.5 6 2.8 1.0 6.0 Related 31 7.6 5.2 10.6 17 8.0 4.7 12.5 Meningism Any 1 0.2 0.0 1.4 0 0.0 0.0 0.9 Grade 3 1 0.2 0.0 1.4 0 0.0 0.0 0.9 N=400 N=207 38.0C 149 37.3 32.5 42.2 69 33.3 27.0 40.2 > 39.5C 22 5.5 3.5 8.2 10 4.8 2.3 8.7 Related 63 15.8 12.3 19.7 26 12.6 8.4 17.9 Rash Any 51 12.8 9.6 16.4 16 7.7 4.5 12.2 Grade 3 3 0.8 0.2 2.2 4 1.9 0.5 4.9 Related 12 3.0 1.6 5.2 5 2.4 0.8 5.5 Meningism N= number of subjects with an administered dose n(%)= number(percentage) of subjects for whom the symptom was reported at least once 95%CI= Exact 95% confidence interval; LL = lower limit, UL = upper limit Any: any solicited general symptom irrespective of intensity grade or relationship to vaccination Grade 3 Parotid/Salivary gland swelling: swelling with accompanying general symptoms Grade 3 Meningism: symptom that prevented normal, everyday activities Grade 3 rash: >150 lesions Related: symptoms considered by the investigator to have a causal relationship to vaccination Safety Results: Number (%) of subjects with unsolicited adverse events after the first dose (Total Vaccinated Cohort) Most frequent adverse events - On-Therapy (occurring within Day 0-42 following vaccination) N = 407 N = 408 N = 410 MMR_V N = 213 Subjects with any AE(s), n (%) 188 (46.2) 188 (46.1) 204 (49.8) 79 (37.1) Subjects with severe AE(s), n (%) 24 (5.9) 22 (5.4) 30 (7.3) 6 (2.8) Subjects with related AE(s), n (%) 33 (8.1) 25 (6.1) 31 (7.6) 7 (3.3) Teething 30 (7.4) 30 (7.4) 33 (8.0) 12 (5.6) Rhinitis 24 (5.9) 24 (5.9) 33 (8.0) 18 (8.5) Upper respiratory tract infection 20 (4.9) 23 (5.6) 19 (4.6) 9 (4.2) Diarrhea 23 (5.7) 17 (4.2) 20 (4.9) 5 (2.3) Cough 20 (4.9) 15 (3.7) 19 (4.6) 10 (4.7) Irritability 25 (6.1) 12 (2.9) 19 (4.6) 5 (2.3) Otitis media 15 (3.7) 14 (3.4) 20 (4.9) 2 (0.9) Pharyngitis 11 (2.7) 10 (2.5) 16 (3.9) 7 (3.3) Safety Results: Number (%) of subjects with unsolicited adverse events after the second dose (Total Vaccinated Cohort)
Most frequent adverse events - On-Therapy (occurring within Day 0-42 following vaccination) N = 401 N = 404 N = 400 MMR_V N = 207 Subjects with any AE(s), n (%) 154 (38.4) 140 (34.7) 142 (35.5) 71 (34.3) Subjects with Grade 3 AE(s), n (%) 19 (4.7) 8 (2.0) 12 (3.0) 15 (7.2) Subjects with related AE(s), n (%) 10 (2.5) 8 (2.0) 13 (3.3) 2 (1.0) Rhinitis 35 (8.7) 31 (7.7) 27 (6.8) 23 (11.1) Upper respiratory tract infection 23 (5.7) 22 (5.4) 20 (5.0) 11 (5.3) Teething 15 (3.7) 13 (3.2) 20 (5.0) 6 (2.9) Cough 16 (4.0) 13 (3.2) 14 (3.5) 9 (4.3) Diarrhea 12 (3.0) 10 (2.5) 12 (3.0) 3 (1.4) Irritability 7 (1.7) 9 (2.2) 14 (3.5) 4 (1.9) Bronchitis 6 (1.5) 8 (2.0) 7 (1.8) 8 (3.9) Safety Results: Number (%) of subjects with Serious Adverse Events (SAEs) 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 = 407 N = 408 N = 410 MMR_V N = 213 Subjects with any SAE(s), n (%) [n related] 3 (0.7) [0] 4 (1.0) [1] 6 (1.5) [1] 3 (1.4) [0] Gastroenteritis 1 (0.2) [0] 1 (0.2) [0] 0 (0.0) [0] 1 (0.5) [0] Pneumonia 0 (0.0) [0] 0 (0.0) [0] 2 (0.5) [0] 0 (0.0) [0] Animal bite 0 (0.0) [0] 1 (0.2) [0] 0 (0.0) [0] 0 (0.0) [0] Bacterial infection 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0] 1 (0.5) [0] Conjunctivitis 0 (0.0) [0] 1 (0.2) [0] 0 (0.0) [0] 0 (0.0) [0] Contusion 0 (0.0) [0] 1 (0.2) [0] 0 (0.0) [0] 0 (0.0) [0] Croup infectious 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0] 1 (0.5) [0] Drug toxicity 0 (0.0) [0] 0 (0.0) [0] 1 (0.2) [0] 0 (0.0) [0] Febrile convulsion 0 (0.0) [0] 0 (0.0) [0] 1 (0.2) [0] 0 (0.0) [0] Hypersensitivity 0 (0.0) [0] 1 (0.2) [1] 0 (0.0) [0] 0 (0.0) [0] Otitis media 1 (0.2) [0] 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0] Pharyngitis 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0] 1 (0.5) [0] Pharyngotonsillitis 1 (0.2) [0] 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0] Pyelonephritis 1 (0.2) [0] 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0] Pyrexia 0 (0.0) [0] 0 (0.0) [0] 1 (0.2) [1] 0 (0.0) [0] Viral upper respiratory tract infection 0 (0.0) [0] 0 (0.0) [0] 1 (0.2) [0] 0 (0.0) [0] Fatal SAEs N = 407 N = 408 N = 410 MMR_V N = 213 Subjects with fatal SAE(s), n (%) [n related] 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0] Conclusion: Six weeks after, at least 92.8% of subjects had anti-mumps titers cut-off s by neutralization test. At the same time point, at least 95.3%, 99.7% and 95.7% of subjects had anti-measles, anti-rubella and anti-varicella antibody titers cut-off s. Six weeks after, at least 99.4% of subjects had anti-mumps titers cut-off s by neutralization test. At the same time point, at least 98.4% and 97.3% of subjects had anti-measles and anti-varicella antibody titers cut-off s, while all subjects had anti-rubella antibody titers cut-off s. Across doses and groups, redness and fever were the most frequently reported solicited local and general symptoms, respectively. SAEs were reported in 3 (0.7%), 4 (1.0%), 6 (1.5%) and 3 (1.4%) subjects in the,, and MMR_V groups, respectively; 2 of these SAEs, 1 in the group and 1 in the group, were considered by the investigators to be related with the study vaccination. No fatal SAEs were reported during the course of the study. Date updated: 19-December-2016