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.: 347414/017 Title: A multinational, randomised, controlled, single-blind, phase-ii study to evaluate the safety and immunogenicity of two investigational vaccination regimens versus a licensed Haemophilus influenzae type b (Hib) conjugate vaccine (Hiberix ) given concomitantly with DTPw-HBV vaccine in a separate injection to infants at 2, 4, and 6 months of age. Rationale: The aim of this study was to assess the safety and the immune response induced by two investigational vaccination regimens, compared to DTPw-HBV and Hib vaccines administered concomitantly as two separate injections to healthy infants at 2, 4 and 6 months of age. DTPw-HBV = combined diphtheria, tetanus, whole-cell pertussis and hepatitis B vaccine Phase: II Study Period: 4 August 2000 to 21 March 2001 Study Design: Single-blind, phase II, randomised, controlled, multinational study with three parallel groups with unbalanced allocation (1: 2: 4). The investigational vaccination regimens are not currently registered or marketed. Data from the group receiving currently registered vaccines, Hib conjugate and DTPw-HBV vaccines are presented. Data from the investigational vaccination regimens, which are not yet approved or marketed, are not reported at this time. Centres: Two centres in Chile and one centre each in Argentina and Costa Rica Indication: Primary immunisation against Haemophilus influenzae type b, diphtheria, tetanus, pertussis and hepatitis B diseases in healthy infants at 2, 4 and 6 months of age. Treatment: The study groups were as follows: Group A: received the licensed DTPw-HBV and Hib vaccines. Group B: received the investigational vaccination regimen 1. Group C: received the investigational vaccination regimen 2. All vaccines were administered intramuscularly in the right thigh as a 3-dose primary vaccination course at 2, 4 and 6 months of age. DTPw-HBV vaccine was administered intramuscularly in the left thigh concomitantly to all three vaccine groups. Objectives: To assess the safety of two investigational vaccination regimens compared to DTPw-HBV and Hib vaccines administered concomitantly as two separate injections. Primary Outcome/Efficacy Variable: All outcome variables were exploratory. No primary outcome variable was defined in this study. Secondary Outcome/Efficacy Variable(s): Only outcome variables related to the licensed vaccines are presented. Occurrence of any grade 3 solicited symptom within 8 days (day 0 - day 7) after each vaccination. Occurrence of each solicited symptom within 8 days (day 0 - day 7) after each vaccination. Occurrence of unsolicited adverse events within 31 days (day 0 - day 30) after each vaccination. Occurrence of any serious adverse event occurring up to 30 days after the administration of the last vaccine dose. Occurrence of any late serious adverse event occurring from one month after the administration of the last vaccine dose up to six months after the administration of the last vaccine dose. Antibody concentrations against polyribosyl-ribitol-phosphate (anti-prp), two months after the administration of study vaccine dose 2 and one month after the administration of study vaccine dose 3. Anti-diphtheria and anti-tetanus toxoids, anti-bordetella pertussis (anti-bpt), and anti-hepatitis B surface antigen (anti-hbs) antibody concentrations, one month after the administration of study vaccine dose 3. Seroprotection status two months after the administration of study vaccine dose 2 (only for anti-prp) and one month after the administration of study vaccine dose 3, defined as: anti-prp antibody concentrations 0.15 g/ml, 1.0 g/ml anti-diphtheria toxoid antibody concentrations 0.1 IU/ml anti-tetanus toxoid antibody concentrations 0.1 IU/ml anti-hbs antibody concentrations 10 miu/ml Seropositivity status, one month after the administration of study vaccine dose 3, defined as: anti-bpt concentrations 15 EL.U/ml Vaccine response to Bordetella pertussis one month after the study vaccine dose 3, defined as appearance of antibodies in subjects who were initially seronegative (i.e. with concentrations < cut-off value) or at least maintenance
of pre-vaccination antibody concentrations in subjects who were initially seropositive (i.e. with concentrations cutoff value), taking into consideration the decreasing maternal antibodies. Statistical Methods: The analyses were performed on the Total vaccinated cohort. The Total vaccinated cohort included all subjects who received at least one dose of the vaccine. Analysis of immunogenicity: The analysis of immunogenicity was performed on the Total vaccinated cohort on subjects for whom immunogenicity data were available. Geometric Mean concentration (GMCs) and seroprotection rate for anti-prp were calculated at all blood sampling time points with 95% confidence intervals (CI). GMCs and seroprotection rate for anti-diphtheria, anti-tetanus and anti-hbs antibodies were calculated before the first dose and one month after the administration of the third vaccine dose with 95% CI. GMCs and seropositivity rate for anti-bordetella pertussis were calculated before the first dose and one month after the administration of the third vaccine with 95% CI. Vaccine response was calculated for anti-bordetella pertussis one month after the administration of the third vaccine dose with exact 95% CI. Analysis of safety: The analysis of safety was performed on the Total vaccinated cohort on subjects for whom safety data were available. For each solicited symptom, the percentage of subjects with the symptom reported during the 8 day (day 0-day 7) followup period was summarised with exact 95% CI by dose and across doses. The percentage of subjects reporting unsolicited adverse events within 31 days (day 0-day 30) following vaccination was tabulated according to the World Health Organization (WHO) preferred term. The occurrence of the serious adverse events throughout the entire study period and including up to six months after the administration of the last vaccine dose was tabulated according to the MedDRA (Medical Dictionary for Adverse Events) preferred term. Study Population: A male or female between, and including, 6 and 12 weeks of age at the time of the first vaccination, born after a gestation period between 36 and 42 weeks, who was free of obvious health problems as established by medical history and clinical examination before entering into the study. Written informed consent was obtained from the parents or guardians of the subject prior to study entry. The subjects were not previously vaccinated against diphtheria, tetanus, pertussis, hepatitis B and/or Haemophilus influenzae type b and did not have a history of these diseases. Number of Subjects: Planned, N 100 Randomised, N (Total vaccinated cohort) 100 Completed, n (%) 92 (92.0) Total Number Subjects Withdrawn, n (%) 8 (8.0) Withdrawn due to Adverse Events, n (%) 0 (0.0) Withdrawn due to Lack of Efficacy, n (%) Not applicable Withdrawn for other reasons, n (%) 8 (8.0) Demographics N (Total vaccinated cohort) 100 Females: Males 46:54 Mean Age, weeks (SD) 8.4 (1.33) White, n (%) 100 (100) Primary Efficacy Results: Not applicable. Percentage of subjects reporting solicited local symptoms within the 8 day (day 0-day 7) follow-up period after each dose and across doses (Total vaccinated cohort) Symptom Intensity Dose 1 N = 95 Dose 2 N = 94 Pain Any 74 77.9 68.2 85.8 64 68.1 57.7 77.3 Grade 3 20 21.1 13.4 30.6 16 17.0 10.1 26.2 Redness Any 51 53.7 43.2 64.0 52 55.3 44.7 65.6 >30 mm 6 6.3 2.4 13.2 2 2.1 0.3 7.5 Swelling Any 40 42.1 32.0 52.7 40 42.6 32.4 53.2 >30 mm 7 7.4 3.0 14.6 5 5.3 1.7 12.0
Symptom Intensity Dose 3 N = 91 Across Doses Pain Any 58 63.7 53.0 73.6 87 91.6 84.1 96.3 Grade 3 14 15.4 8.7 24.5 39 41.1 31.1 51.6 Redness Any 47 51.6 40.9 62.3 74 77.9 68.2 85.8 >30 mm 4 4.4 1.2 10.9 10 10.5 5.2 18.5 Swelling Any 44 48.4 37.7 59.1 67 70.5 60.3 79.4 >30 mm 3 3.3 0.7 9.3 11 11.6 5.9 19.8 N: number of subjects with at least one symptom sheet completed n (%): number (percentage) of subjects reporting a specific symptom Any: incidence of a particular symptom regardless of grade Grade 3 pain: cried when limb was moved / spontaneously painful 95% CI: exact 95% confidence interval; LL: lower limit, UL: upper limit * Five subjects were lost to follow-up without any safety information reported Percentage of subjects reporting solicited general symptoms within the 8 day (day 0-day 7) follow-up period after each dose and across doses (Total vaccinated cohort) Symptom Intensity/ Relationship Dose 1 N = 95 Dose 2 N = 94 Drowsiness Any 56 58.9 48.4 68.9 49 52.1 41.6 62.5 Grade 3 5 5.3 1.7 11.9 7 7.4 3.0 14.7 Related 41 43.2 33.0 53.7 37 39.4 29.4 50.0 Irritability Any 71 74.7 64.8 83.1 65 69.1 58.8 78.3 Grade 3 9 9.5 4.4 17.2 12 12.8 6.8 21.2 Related 56 58.9 48.4 68.9 51 54.3 43.7 64.6 Loss of appetite Fever (Rectal) Any 32 33.7 24.3 44.1 30 31.9 22.7 42.3 Grade 3 1 1.1 0.0 5.7 3 3.2 0.7 9.0 Related 23 24.2 16.0 34.1 21 22.3 14.4 32.1 38 C 41 43.2 33.0 53.7 47 50.0 39.5 60.5 >40 C 1 1.1 0.0 5.7 1 1.1 0.0 5.8 Related 31 32.6 23.4 43.0 40 42.6 32.4 53.2 Symptom Intensity/ Relationship Dose 3 N = 91 Across Doses Drowsiness Any 44 48.4 37.7 59.1 76 80.0 70.5 87.5 Grade 3 5 5.5 1.8 12.4 14 14.7 8.3 23.5 Related 36 39.6 29.5 50.4 58 61.1 50.5 70.9 Irritability Any 55 60.4 49.6 70.5 84 88.4 80.2 94.1 Grade 3 8 8.8 3.9 16.6 22 23.2 15.1 32.9 Related 45 49.5 38.8 60.1 68 71.6 61.4 80.4 Loss of appetite Fever (Rectal) Any 26 28.6 19.6 39.0 57 60.0 49.4 69.9 Grade 3 1 1.1 0.0 6.0 5 5.3 1.7 11.9 Related 21 23.1 14.9 33.1 44 46.3 36.0 56.8 38 C 49 53.8 43.1 64.4 77 81.1 71.7 88.4 >40 C 1 1.1 0.0 6.0 3 3.2 0.7 9.0 Related 37 40.7 30.5 51.5 62 65.3 54.8 74.7
N: number of subjects with at least one symptom sheet completed n (%): number (percentage) of subjects reporting a specific symptom Any: incidence of a particular symptom regardless of grade or relationship to vaccination Related: symptoms considered by the investigator to have a causal relationship to study vaccination Grade 3: symptom which prevented normal everyday activities 95% CI: exact 95% confidence interval; LL: lower limit, UL: upper limit * Five subjects were lost to follow-up without any safety information reported Seroprotection rate and GMCs for anti-prp antibodies before the first vaccine dose, two months after dose 2 and one month after dose 3 vaccination (Total vaccinated cohort) Timing N 0.15 g/ml 1.0 g/ml GMC n % 95% CI n % 95% CI g/ml 95% CI LL UL Pre 100 34 34.0 24.8 44.2 8 8.0 3.5 15.2 0.145 0.117 0.179 PII(M4) 94 88 93.6 86.6 97.6 64 68.1 57.7 77.3 2.552 1.755 3.711 PIII(M5) 92 92 100.0 96.1 100.0 89 96.7 90.8 99.3 18.317 14.066 23.854 n (%): number (percentage) of subjects with concentrations within the specified range PII(M4): Blood samples obtained after dose 2, at month 4 after the first dose PIII(M5): Blood samples obtained after dose 3, at month 5 after the first dose Seroprotection rate and GMCs for anti-diphtheria, anti-tetanus antibodies before the first vaccine dose and one month after the administration of the vaccine dose 3 (Total vaccinated cohort) Antibody Timing N 0.1 IU/ml GMC n % 95% CI IU/ml 95% CI Anti-diphtheria Pre 99 37 37.4 27.9 47.7 0.117 0.091 0.151 PIII(M5) 87 86 98.9 93.8 100.0 2.394 1.949 2.940 Anti-tetanus Pre 98 63 64.3 54.0 73.7 0.300 0.214 0.421 PIII(M5) 87 87 100.0 95.8 100.0 2.233 1.739 2.868 n (%): number (percentage) of subjects with concentrations within the specified range PIII(M5): Blood samples obtained after dose 3, at month 5 after the first dose Seroprotection rate and GMCs for anti-hbs antibodies before the first vaccine dose and one month after the administration of the vaccine dose 3 (Total vaccinated cohort) Timing N 10 miu/ml GMC n % 95% CI miu/ml 95% CI Pre 93 0 0.0 0.0 3.9 5.0 5.0 5.0 PIII(M5) 84 83 98.8 93.5 100.0 2016.0 1483.0 2740.5 n (%): number (percentage) of subjects with concentrations within the specified range PIII(M5): Blood samples obtained after dose 3, at month 5 after the first dose Seropositivity rate and GMCs for anti-bordetella pertussis antibodies before the first vaccine dose and one month after the administration of the vaccine dose 3 (Total vaccinated cohort) Timing N 15 EL.U/ml GMC n % 95% CI EL.U/ml 95% CI
Pre 98 3 3.1 0.6 8.7 7.726 7.463 7.999 PIII(M5) 87 87 100.0 95.8 100.0 158.680 138.449 181.867 n (%): number (percentage) of subjects with concentrations 15 EL.U/ml PIII (M5): Blood samples obtained after dose 3, at month 5 after the first dose. Secondary Outcome Variable (s): Vaccine response to anti-bordetella pertussis one month after the administration of the vaccine dose 3 (Total vaccinated cohort) Pre-vaccination status Number of Subjects* Responders n % 95% CI LL UL S+ 2 2 100 - - S- 84 84 100 - - Total 86 86 100 95.8 100 * number of subjects with both pre- and post-vaccination results available n (%): number (percentage) of responders 95%CI: exact 95% confidence interval; LL: lower limit; UL: upper limit S-/ S+: seronegative/ seropositive subjects at pre-vaccination Total: subjects either seropositive or seronegative at pre-vaccination Safety Results: Number (%) of subjects with unsolicited adverse events (Total vaccinated cohort) Most Frequent Adverse Events On-Therapy- (occurring within day 0-30 following vaccination) Subjects with any AE(s), n (%) 44 (46.3) Bronchitis 15 (15.8) Diarrhoea 9 (9.5) Upper respiratory tract infection 8 (8.4) Rhinitis 7 (7.4) Pharyngitis 6 (6.3) Otitis media 4 (4.2) Pneumonia 3 (3.2) Coughing 2 (2.1) Dermatitis 2 (2.1) Gastroesophageal reflux 2 (2.1) Infection 2 (2.1) Moniliasis 2 (2.1) Urticaria 2 (2.1) * Five subjects were lost to follow-up without any AE reported Safety Results: Number (%) of subjects with serious adverse events reported up to Day 30 after vaccination (from day 0 to day 30) (Total vaccinated cohort) Serious adverse event, n (%) [n considered by the investigator to be related to study medication] All SAEs Subjects with any SAE(s), n (%) [n related] 3 (3.2) [0] Gastroenteritis 1 (1.1) [0] Hypovolaemic shock 1 (1.1) [0] Partial seizures 1 (1.1) [0] Pneumonia 1 (1.1) [0] * Five subjects were lost to follow-up without any SAE reported Safety Results: Number (%) of subjects with serious adverse events reported from Day 31 after vaccination to Month 6 (Total vaccinated cohort) Serious adverse event, n (%) [n considered by the investigator to be related to study medication] All SAEs Subjects with any SAE(s), n (%) [n related] 3 (3.2) [0]
Apnoea 1 (1.1) [0] Pleural effusion 1 (1.1) [0] Pneumonia 1 (1.1) [0] Pneumonia viral 1 (1.1) [0] Urinary tract infection 1 (1.1) [0] * Five subjects were lost to follow-up without any SAE reported Serious adverse event, n (%) [n considered by the investigator to be related to study medication] Fatal SAEs Subjects with fatal SAEs, n (%) [related] 0 (0.0) [0] * Five subjects were lost to follow-up without SAE reported Conclusion: The most frequently reported solicited local symptom was pain at injection site and the most frequently reported solicited general symptom was drowsiness. Pain at the injection site was also the most frequently reported grade 3 solicited local symptom. For the group presented, one month after Dose 3, all subjects had anti-prp antibody concentrations 0.15 g/ml and at least 96.7% of the subjects had antibody concentrations 1.0 g/ml. All subjects were seroprotected for anti-tetanus and seropositive for Bordetella pertussis antibodies. At least 98.8% of the subjects were seroprotected for anti-diphtheria and anti-hbs antibodies. The most frequently reported unsolicited adverse events were bronchitis (15.8%) followed by diarrhoea (9.5%) and upper respiratory tract infection (8.4%). Serious adverse events were reported in 5 subjects, none of which was fatal. Date Updated: 24-April-2015