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.: 217744/012 (DTPa-HBV-IPV-012) Title: Randomised clinical study to assess the immunogenicity and reactogenicity of SB Biologicals' DTPa-HBV-IPV vaccine, when co-administered with Hib vaccine in two concomitant injections into opposite limbs, as a primary vaccination course to healthy infants at the age of 3, 4½ and 6 months Rationale: Vaccination of infants against diphtheria, tetanus and pertussis is well established in some countries, as well as routine poliovirus vaccination. There is growing demand for universal vaccination against hepatitis B. Combined administration of diphtheria, tetanus, acellular pertussis, hepatitis B and inactivated poliovirus vaccine in a single injection would promote vaccination compliance and offer more comfort to the vaccinee. Phase: III Study Period: 9 November 1995 to 2 July 1996 Study Design: Open study with four groups: Group 1 : DTPa-HBV-IPV + SB Hib Group 2 : DTPa-HBV-IPV + manufacturer A s Hib Group 3 : DTPa-HBV-IPV + manufacturer B s Hib Group 4 : dose 1 & 3 DTPa-HBV-IPV + manufacturer C s Hib; dose 2 :DTPa-HBV-IPV* * No Hib vaccine was administered in this group at the DTPa-HBV-IPV second dose since manufacturer C s Hib is recommended as a two-dose primary vaccination schedule. DTPa = diphtheria, tetanus, acellular pertussis; HBV = hepatitis B vaccine; IPV = inactivated poliovirus vaccine; Hib = Haemophilus influenzae type b conjugate vaccine (Hib) Centres: Two sites in Lithuania Indication: Primary vaccination of healthy infants at 3 ½, 4 and 6 months of age Treatment: Study vaccines Vaccination schedule: 3, 4 1/2 and 6 months of age. Route of administration: Intramuscular injection of DTPa-HBV-IPV vaccine into the right anterolateral thigh and an intramuscular injection of Hib vaccine into the left anterolateral thigh Objectives: The primary objective was: to assess the immunogenicity of DTPa-HBV-IPV vaccine in all groups. The secondary objectives were: to assess the reactogenicity of DTPa-HBV-IPV vaccine in all groups. to evaluate the immunogenicity of the Hib vaccines co-administered in all groups. to evaluate the reactogenicity of the Hib vaccines co-administered in all groups. Primary Outcome/Efficacy Variable: Immunogenicity: Measurement of serum titres/concentrations of antibodies against all study vaccine antigen components in all vaccinees before the first dose and one month after the third dose. Antibodies to diphtheria and tetanus toxoids were measured by ELISA with a cut-off of 0.1 IU/mL and antibodies to HBsAg were measured using a radio-immunoassay with a cut-off of 10 miu/ml. Serum antibody concentrations against pertussis antigens were determined by ELISA with a cut-off of 5 EL.U/mL. Vaccine response to the pertussis antigens was defined as the induction of an antibody response to the individual pertussis antigens, taking into account the pre-vaccination serological status of the subject. For initially seronegative subjects, an antibody response was indicated by a post IIIvaccination antibody concentration greater than or equal to the assay cut-off. For initially seropositive subjects, an antibody response was indicated by a post III-vaccination antibody concentration at least equal to the pre-vaccination concentration. Neutralising antibodies against poliomyelitis virus types 1, 2 and 3 were determined based on a microneutralisation test and results were expressed as a titre which was the reciprocal of the highest dilution of serum showing 50% virus neutralizing effect. Sera were tested starting at a 1/8 dilution and subjects with virus neutralizing titres (VN dil) < 8 were considered as seronegative whereas subjects with (VN dil) titres 8 were considered as seropositive. Secondary Outcome/Efficacy Variables: Immunogenicity: Total antibodies to the Hib polysaccharide, polyribose-ribitol-phosphate (PRP) were measured by - 1 -
Radio labelled Antigen Binding Assay. The cut-off of the test is 0.15 µg/ml. The percentage of subjects with a serum antibody concentration for anti-prp 0.15µg/mL and 1.0 µg/ml was determined. Reactogenicity: Recording of solicited local (pain on digital pressure, redness and swelling) and general (fever, unusual, unexplained crying for more than one hour, vomiting, diarrhoea, loss of appetite, and restlessness or sleeping less than usual) adverse experiences by the parents/guardians during a four-day follow-up period after each vaccination. Also, recording of unsolicited adverse reactions during the 30 day follow-up period after each vaccination and serious adverse events (SAEs) during the entire study period. Statistical Methods: The intention-to-treat (ITT) cohort consisted of all subjects for whom data were available.. The according-to-protocol (ATP) cohort for immunogenicity included all subjects who fulfilled the criteria defined in the protocol. Analysis of immunogenicity: The primary analysis of immunogenicity was performed on the ATP cohort for immunogenicity. A secondary analysis was performed on the ITT cohort. Pre- and post-vaccination seropositivity/seroprotection rates (%) and vaccine response rates for anti-pertussis antibodies were summarized by group. Geometric mean antibody titres/geometric mean antibody concentrations (GMTs/GMCs) were calculated, with the 95% confidence interval (CI), for all vaccine components at each point that blood samples were taken, by taking the log-transformation of individual titres/concentrations and calculating the anti-log of the mean of these transformed values. Antibody titres/concentrations below the assay cut-off were given an arbitrary value of one half of the cut-off value. Analysis of safety: The analysis of safety was conducted on the ITT cohort. For each treatment group, the percentage of doses with solicited symptoms (any, local, general and each specific symptom) over the full vaccination course was tabulated with its 95% confidence interval (CI). The percentage of subjects experiencing unsolicited symptoms within 30 days after any vaccine dose, classified by WHO Preferred Terms, was tabulated by groups. Study Population: Healthy infants, aged 12 to 16 weeks at the time of the first vaccination. Number of Subjects Group 1 Group 2 Group 3 Group 4 Planned, N 220 110 110 110 Randomized, N (%) 219 (100.0) 110 (100.0) 110 (100.0) 110 (100.0) Completed, n (%) 217 (99.09) 106 (96.36) 109 (99.09) 10 9 (99.09) Total Number Subjects Withdrawn, 2 (0.91) 4 (3.64) 1 (0.91) 1 (0.91) n (%) Withdrawn due to Adverse Events n 0 (0) 1 (0.91) 0 (0) 0 (0) (%) Withdrawn due to Lack of Efficacy n not applicable not applicable not applicable not applicable (%) Withdrawn for other reasons n (%) 2 (0.91) 3 (2.73) 1 (0.91) 1 (0.91) Demographics Group 1 Group 2 Group 3 Group 4 N (ITT) 219 110 110 110 Females: Males 116:103 45:65 46:64 55:55 Mean Age, weeks (SD) 13.2 (1.12) 13.4 (1.05) 13.2 (1.12) 13.2 (1.09) Caucasian, n (%) 219 (100) 110 (100) 110 (100) 110 (100) Primary Efficacy Results: Seroprotection rates (%) and GMCs for anti-diphtheria antibodies (ATP cohort for immunogenicity) Group Timing N %S+ 95 % CI GMC 95 % CI n % LL UL IU/mL LL UL 1 Pre 202 75 37.1 30.2 44.0 0.088 0.078 0.099 PIII 202 202 100.0 97.7 100.0 1.412 1.265 1.576 2 Pre 102 29 28.4 20.2 38.4 0.073 0.064 0.084 PIII 102 102 100.0 95.5 100.0 1.672 1.440 1.941 3 Pre 100 33 33.0 23.3 42.7 0.076 0.067 0.086 PIII 100 100 100.0 95.4 100.0 1.797 1.554 2.076 4 Pre 105 26 24.8 17.1 34.3 0.072 0.062 0.082 PIII 105 105 100.0 95.6 100.0 1.615 1.393 1.874-2 -
Pre = pre-vaccination; PIII = approximately one month after the third dose %S+ = seroprotection rate n/% = number/percentage of subjects with anti-diphtheria antibody concentrations 0.1 IU/m. 95% CI, LL and UL= 95% confidence interval, upper and lower limits Seroprotection rates (%) and GMCs of anti-tetanus antibodies (ATP cohort for immunogenicity) Group Timing N %S+ 95 % CI GMC 95 % CI n % LL UL IU/mL LL UL 1 Pre 202 91 45.0 37.9 52.2 0.114 0.098 0.131 PIII 199 199 100.0 97.6 100.0 1.946 1.748 2.167 2 Pre 102 43 42.2 32.1 52.2 0.100 0.083 0.121 PIII 101 101 100.0 95.4 100.0 2.463 2.127 2.851 3 Pre 100 55 55.0 44.7 65.3 0.123 0.101 0.149 PIII 98 98 100.0 95.3 100.0 2.393 2.065 2.774 4 Pre 105 45 42.9 32.9 52.8 0.101 0.085 0.122 PIII 103 103 100.0 95.5 100.0 2.604 2.287 2.965 Pre = pre-vaccination; PIII = approximately one month after the third dose %S+ = seroprotection rate n/% = number/percentage of subjects with anti-tetanus antibody concentrations 0.1 IU/mL. 95% CI, LL and UL= 95% confidence interval, upper and lower limits Vaccine response according to pre-vaccination status (ATP cohort for immunogenicity) Pre-vaccination status Vaccine response (Post) Antibody Group Pre N n % 95% CI LL UL Anti-PT 1 S- 158 158 100 S+ 37 37 100 Total 195 195 100 97.6 100 2 S- 89 89 100 S+ 12 12 100 Total 101 101 100 95.4 100 3 S- 70 70 100 S+ 25 24 96.0 Total 95 94 98.9 93.4 99.9 4 S- 86 86 100 S+ 17 17 100 Total 103 103 100 95.5 100 Anti-FHA 1 S- 68 68 100 S+ 115 115 100 Total 183 183 100 97.4 100 2 S- 34 34 100 S+ 58 57 98.3 Total 92 91 98.9 93.2 99.9 3 S- 36 36 100 S+ 55 53 96.4 Total 91 89 97.8 91.5 99.6 4 S- 33 33 100 S+ 62 59 95.2 Total 95 92 96.8 90.3 99.2 Anti-PRN 1 S- 147 147 100 S+ 52 50 96.2 Total 199 197 99 96.0 99.8 2 S- 76 76 100 S+ 25 24 96.0 Total 101 100 99 93.8 99.9-3 -
3 S- 69 69 100 S+ 29 24 82.8 Total 98 93 94.9 87.9 98.1 4 S- 72 72 100 S+ 31 30 96.8 Total 103 102 99 93.9 99.9 Pre = pre-vaccination serological status; Post = approximately one month after the third dose n/% = number/percentage of subjects with a vaccine response 95% CI, LL and UL= 95% confidence interval, upper and lower limits Vaccine response was calculated only for subjects who had pre and post results available. Vaccine response definition : - pre-vaccination seronegative subjects: appearance of antibodies (i.e. concentration cut-off 5 EL.U/mL) - pre-vaccination seropositive subjects: post-vaccination concentration pre-vaccination concentration Pre- and post-vaccination seropositivity rates and GMCs for each pertussis antigen (ATP cohort for immunogenicity) Antibody Group Timing N %S+ 95 % CI GMC 95 % CI n % LL UL EL U/mL LL UL Anti-PT 1 Pre 198 39 19.7 14.5 26.1 3.2 3.0 3.5 PIII 199 199 100 97.6 100 82.3 76.9 88.0 2 Pre 102 12 11.8 6.5 20.0 2.9 2.7 3.1 PIII 101 101 100 95.4 100 90.2 81.5 99.7 3 Pre 97 25 25.8 17.7 35.8 3.6 3.1 4.1 PIII 98 98 100 95.3 100 83.2 75.1 92.0 4 Pre 105 17 16.2 10.0 24.9 3.1 2.8 3.5 PIII 103 103 100 95.5 100 81.5 73.6 90.2 Anti-FHA 1 Pre 189 118 62.4 55.3 69.6 6.6 5.8 7.6 PIII 195 195 100 97.6 100 113.2 103.8 123.4 2 Pre 93 59 63.4 53.1 73.8 7.1 5.8 8.7 PIII 101 101 100 95.4 100 107.9 95.6 121.7 3 Pre 95 56 58.9 48.5 69.4 7.4 6.0 9.1 PIII 95 95 100 95.2 100 102.9 90.4 117.1 4 Pre 100 65 65.0 55.2 74.8 7.4 6.1 9.1 PIII 100 100 100 95.4 100 99.3 86.8 113.5 Anti-PRN 1 Pre 202 53 26.2 20.4 33.0 3.8 3.4 4.2 PIII 199 199 100 97.6 100 154.6 138.8 172.1 2 Pre 102 25 24.5 16.8 34.2 3.5 3.1 4.0 PIII 101 101 100 95.4 100 165.5 142.8 191.7 3 Pre 100 30 30.0 20.5 39.5 4.1 3.4 4.8 PIII 98 98 100 95.3 100 149.9 127.5 176.1 4 Pre 105 31 29.5 21.2 39.3 3.8 3.3 4.3 PIII 103 103 100 95.5 100 153.2 132.8 176.6 Pre = pre-vaccination; PIII = approximately one month after the third dose %S+ = seropositivity rate n/% = number/percentage of subjects with anti-pertussis antibody concentrations 5 EL.U/mL. 95% CI, LL and UL= 95% confidence interval, upper and lower limits Seroprotection rates (%) and GMCs of anti-hbs antibodies (ATP cohort for immunogenicity) Group Timing N %S+ 95 % CI GMC 95 % CI n % LL UL miu/ml LL UL 1 Pre 202 17 8.4 5.1 13.4 6.7 5.8 7.7 PIII 202 202 100.0 97.7 100.0 970.0 825.7 1139.5 2 Pre 102 10 9.8 5.1 17.7 6.8 5.5 8.4 PIII 101 101 100.0 95.4 100.0 1038.9 806.7 1338.1 3 Pre 100 11 11.0 5.9 19.2 7.3 5.7 9.3 PIII 99 98 99.0 93.7 99.9 797.7 611.9 1039.8-4 -
4 Pre 105 7 6.7 3.0 13.7 6.1 5.1 7.3 PIII 105 104 99.0 94.0 100.0 720.5 562.2 923.2 Pre = pre-vaccination; PIII = approximately one month after the third dose %S+ = seropositivity rate n/% = number/percentage of subjects with anti-hbs antibody titres 10mIU/mL. 95% CI, LL and UL = 95% confidence interval, upper and lower limits Seropositivity rates (%) and GMTs for anti-poliovirus antibodies (ATP cohort for immunogenicity) Antibody Group Timing N %S+ 95 % CI GMT 95 % CI n % LL UL LL UL Anti-poliovirus 1 PIII 201 201 100 97.7 100 354.2 309.4 405.3 type 1 2 PIII 101 101 100 95.4 100 323.3 266.8 391.9 3 PIII 99 99 100 95.3 100 287.4 240.7 343.2 4 PIII 104 104 100 95.6 100 330.9 280.4 390.5 Anti-poliovirus 1 PIII 201 201 100 97.7 100 297.0 257.5 342.6 type 2 2 PIII 101 101 100 95.4 100 314.7 254.9 388.4 3 PIII 99 99 100 95.3 100 231.4 185.7 288.3 4 PIII 104 104 100 95.6 100 269.2 224.0 323.6 Anti-poliovirus 1 PIII 201 201 100 97.7 100 920.1 813.0 1041.4 type 3 2 PIII 101 101 100 95.4 100 905.0 746.6 1097.1 3 PIII 99 99 100 95.3 100 812.7 676.2 976.8 4 PIII 104 104 100 95.6 100 800.2 672.6 951.9 Pre = pre-vaccination; PIII = approximately one month after the third dose %S+ = seropositivity rate n/% = number/percentage of subjects with anti-poliovirus antibody titres 8. 95% CI, LL and UL = 95% confidence interval, upper and lower limits Note: Only PIII blood samples were analyzed for anti-poliovirus antibodies Distribution of individual anti-prp antibody concentrations and GMCs (ATP cohort for immunogenicity) 0.15 µg/ml 95% CI 1.0 µg/ml 95% CI GMC (µg/ml) 95% CI Group Timing N n % LL UL n % LL UL LL UL 1 Pre 202 65 32.2 25.5 38.9 8 4.0 1.9 7.9 0.132 0.116 0.150 PIII 202 202 100 97.7 100 194 96.0 92.1 98.1 7.198 6.236 8.307 2 Pre 102 25 24.5 16.8 34.2 6 5.9 2.4 12.9 0.115 0.097 0.135 PIII 101 100 99.0 93.8 99.9 95 94.1 87.0 97.6 6.661 5.437 8.161 3 Pre 100 35 35.0 25.2 44.8 9 9.0 4.5 16.8 0.144 0.117 0.176 PIII 100 100 100 95.4 100 88 88.0 79.6 93.4 5.770 4.422 7.529 4 Pre 105 32 30.5 21.2 39.8 5 4.8 1.8 11.3 0.124 0.105 0.146 PIII 105 105 100 95.6 100 95 90.5 82.8 95.1 4.953 4.015 6.110 Pre = pre-vaccination; PIII = approximately one month after the third dose n/% = number/percentage of subjects with concentrations above the specified cut-off 95% CI, LL and UL = 95% confidence interval, upper and lower limits Secondary Outcome Variables: Number/percentage of subjects reporting each solicited local symptom during the 4-day follow-up period by vaccine group, by dose and across doses (ITT cohort) Group 1 Group 2 95% CI 95% CI Dose Symptom n % LL UL n % LL UL 1 N 219 110 Pain Any 30 13.7 9.4 19.0 23 20.9 13.7 29.7 Grade 3 0 0.0 0.0 1.7 3 2.7 0.6 7.8 Redness Any 78 35.6 29.3 42.3 40 36.4 27.4 46.1 Grade 3 6 2.7 1.0 5.9 4 3.6 1.0 9.0-5 -
Swelling Any 55 25.1 19.5 31.4 29 26.4 18.4 35.6 Grade 3 13 5.9 3.2 9.9 6 5.5 2.0 11.5 2 N 218 107 Pain Any 36 16.5 11.8 22.1 23 21.5 14.1 30.5 Grade 3 0 0.0 0.0 1.7 2 1.9 0.2 6.6 Redness Any 114 52.3 45.4 59.1 66 61.7 51.8 70.9 Grade 3 15 6.9 3.9 11.1 14 13.1 7.3 21.0 Swelling Any 89 40.8 34.2 47.7 47 43.9 34.3 53.9 Grade 3 20 9.2 5.7 13.8 14 13.1 7.3 21.0 3 N 218 106 Pain Any 28 12.8 8.7 18.0 24 22.6 15.1 31.8 Grade 3 1 0.5 0.0 2.5 0 0.0 0.0 3.4 Redness Any 113 51.8 45.0 58.6 56 52.8 42.9 62.6 Grade 3 19 8.7 5.3 13.3 7 6.6 2.7 13.1 Swelling Any 88 40.4 33.8 47.2 42 39.6 30.3 49.6 Grade 3 17 7.8 4.6 12.2 8 7.5 3.3 14.3 Across N 219 110 Doses Pain Any 67 30.6 24.6 37.2 41 37.3 28.2 47.0 Grade 3 1 0.5 0.0 2.5 5 4.5 1.5 10.3 Redness Any 147 67.1 60.5 73.3 79 71.8 62.4 80.0 Grade 3 34 15.5 11.0 21.0 19 17.3 10.7 25.7 Swelling Any 119 54.3 47.5 61.1 60 54.5 44.8 64.1 Grade 3 35 16.0 11.4 21.5 17 15.5 9.3 23.6 Group 3 Group 4 95% CI 95% CI Dose Symptom n % LL UL n % LL UL 1 N 110 110 Pain Any 18 16.4 10.0 24.6 24 21.8 14.5 30.7 Redness Any 42 38.2 29.1 47.9 57 51.8 42.1 61.4 Grade 3 6 5.5 2.0 11.5 1 0.9 0.0 5.0 Swelling Any 28 25.5 17.6 34.6 30 27.3 19.2 36.6 Grade 3 7 6.4 2.6 12.7 3 2.7 0.6 7.8 2 N 109 110 Pain Any 18 16.5 10.1 24.8 21 19.1 12.2 27.7 Redness Any 65 59.6 49.8 68.9 62 56.4 46.6 65.8 Grade 3 9 8.3 3.8 15.1 11 10.0 5.1 17.2 Swelling Any 55 50.5 40.7 60.2 46 41.8 32.5 51.6 Grade 3 10 9.2 4.5 16.2 10 9.1 4.4 16.1 3 N 109 109 Pain Any 13 11.9 6.5 19.5 23 21.1 13.9 30.0 Redness Any 52 47.7 38.1 57.5 66 60.6 50.7 69.8 Grade 3 9 8.3 3.8 15.1 7 6.4 2.6 12.8 Swelling Any 42 38.5 29.4 48.3 49 45.0 35.4 54.8 Grade 3 5 4.6 1.5 10.4 6 5.5 2.0 11.6 Across N 110 110 Doses Pain Any 32 29.1 20.8 38.5 44 40.0 30.8 49.8-6 -
Redness Any 84 76.4 67.3 83.9 85 77.3 68.3 84.7 Grade 3 20 18.2 11.5 26.7 16 14.5 8.5 22.5 Swelling Any 69 62.7 53.0 71.8 62 56.4 46.6 65.8 Grade 3 15 13.6 7.8 21.5 15 13.6 7.8 21.5 Number/percentage of subjects reporting each solicited general symptom during the 4-day follow-up period by vaccine group, by dose and across doses (ITT cohort) Group 1 Group 2 95% CI 95% CI Dose Symptom n % LL UL n % LL UL 1 N 219 110 Diarrhoea Any 24 11.0 7.1 15.9 19 17.3 10.7 25.7 Grade 3 0 0.0 0.0 1.7 0 0.0 0.0 3.3 Related 21 9.6 6.0 14.3 18 16.4 10.0 24.6 Loss of Appetite Any 39 17.8 13.0 23.5 26 23.6 16.1 32.7 Grade 3 1 0.5 0.0 2.5 1 0.9 0.0 5.0 Related 37 16.9 12.2 22.5 26 23.6 16.1 32.7 Restlessness Any 106 48.4 41.6 55.2 71 64.5 54.9 73.4 Grade 3 5 2.3 0.7 5.2 6 5.5 2.0 11.5 Related 105 47.9 41.2 54.8 69 62.7 53.0 71.8 Fever (rectal) Any 19 8.7 5.3 13.2 16 14.5 8.5 22.5 Grade 3 0 0.0 0.0 1.7 0 0.0 0.0 3.3 Related 18 8.2 4.9 12.7 16 14.5 8.5 22.5 Unusual Crying Any 40 18.3 13.4 24.0 43 39.1 29.9 48.9 Grade 3 3 1.4 0.3 4.0 6 5.5 2.0 11.5 Related 39 17.8 13.0 23.5 42 38.2 29.1 47.9 Vomiting Any 21 9.6 6.0 14.3 10 9.1 4.4 16.1 Grade 3 1 0.5 0.0 2.5 0 0.0 0.0 3.3 Related 19 8.7 5.3 13.2 10 9.1 4.4 16.1 2 N 218 107 Diarrhoea Any 16 7.3 4.3 11.6 5 4.7 1.5 10.6 Grade 3 0 0.0 0.0 1.7 1 0.9 0.0 5.1 Related 16 7.3 4.3 11.6 4 3.7 1.0 9.3 Loss of Appetite Any 34 15.6 11.0 21.1 25 23.4 15.7 32.5 Grade 3 1 0.5 0.0 2.5 0 0.0 0.0 3.4 Related 34 15.6 11.0 21.1 25 23.4 15.7 32.5 Restlessness Any 88 40.4 33.8 47.2 46 43.0 33.5 52.9 Grade 3 6 2.8 1.0 5.9 2 1.9 0.2 6.6 Related 86 39.4 32.9 46.3 44 41.1 31.7 51.0 Fever (rectal) Any 18 8.3 5.0 12.7 12 11.2 5.9 18.8 Grade 3 0 0.0 0.0 1.7 1 0.9 0.0 5.1 Related 16 7.3 4.3 11.6 12 11.2 5.9 18.8 Unusual Crying Any 40 18.3 13.4 24.1 24 22.4 14.9 31.5 Grade 3 3 1.4 0.3 4.0 3 2.8 0.6 8.0 Related 40 18.3 13.4 24.1 23 21.5 14.1 30.5 Vomiting Any 12 5.5 2.9 9.4 4 3.7 1.0 9.3 Grade 3 0 0.0 0.0 1.7 1 0.9 0.0 5.1 Related 11 5.0 2.5 8.8 3 2.8 0.6 8.0 3 N 218 106 Diarrhoea Any 12 5.5 2.9 9.4 4 3.8 1.0 9.4 Grade 3 0 0.0 0.0 1.7 0 0.0 0.0 3.4-7 -
Related 11 5.0 2.5 8.8 4 3.8 1.0 9.4 Loss of Appetite Any 22 10.1 6.4 14.9 17 16.0 9.6 24.4 Grade 3 0 0.0 0.0 1.7 1 0.9 0.0 5.1 Related 20 9.2 5.7 13.8 15 14.2 8.1 22.3 Restlessness Any 65 29.8 23.8 36.4 38 35.8 26.8 45.7 Grade 3 1 0.5 0.0 2.5 3 2.8 0.6 8.0 Related 64 29.4 23.4 35.9 36 34.0 25.0 43.8 Fever (rectal) Any 14 6.4 3.6 10.5 10 9.4 4.6 16.7 Grade 3 0 0.0 0.0 1.7 0 0.0 0.0 3.4 Related 13 6.0 3.2 10.0 9 8.5 4.0 15.5 Unusual Crying Any 19 8.7 5.3 13.3 18 17.0 10.4 25.5 Grade 3 1 0.5 0.0 2.5 3 2.8 0.6 8.0 Related 19 8.7 5.3 13.3 17 16.0 9.6 24.4 Vomiting Any 10 4.6 2.2 8.3 2 1.9 0.2 6.6 Grade 3 0 0.0 0.0 1.7 0 0.0 0.0 3.4 Related 10 4.6 2.2 8.3 1 0.9 0.0 5.1 Across N 219 110 Doses Diarrhoea Any 42 19.2 14.2 25.0 28 25.5 17.6 34.6 Grade 3 0 0.0 0.0 1.7 1 0.9 0.0 5.0 Related 41 18.7 13.8 24.5 26 23.6 16.1 32.7 Loss of Appetite Any 71 32.4 26.3 39.1 43 39.1 29.9 48.9 Grade 3 2 0.9 0.1 3.3 2 1.8 0.2 6.4 Related 68 31.1 25.0 37.6 42 38.2 29.1 47.9 Restlessness Any 145 66.2 59.5 72.4 83 75.5 66.3 83.2 Grade 3 12 5.5 2.9 9.4 10 9.1 4.4 16.1 Related 143 65.3 58.6 71.6 82 74.5 65.4 82.4 Fever (rectal) Any 39 17.8 13.0 23.5 24 21.8 14.5 30.7 Grade 3 0 0.0 0.0 1.7 1 0.9 0.0 5.0 Related 37 16.9 12.2 22.5 24 21.8 14.5 30.7 Unusual Crying Any 66 30.1 24.1 36.7 53 48.2 38.6 57.9 Grade 3 7 3.2 1.3 6.5 10 9.1 4.4 16.1 Related 65 29.7 23.7 36.2 52 47.3 37.7 57.0 Vomiting Any 32 14.6 10.2 20.0 15 13.6 7.8 21.5 Grade 3 1 0.5 0.0 2.5 1 0.9 0.0 5.0 Related 31 14.2 9.8 19.5 14 12.7 7.1 20.4 Group 3 Group 4 95% CI 95% CI Dose Symptom n % LL UL n % LL UL 1 N 110 110 Diarrhoea Any 16 14.5 8.5 22.5 15 13.6 7.8 21.5 Related 14 12.7 7.1 20.4 15 13.6 7.8 21.5 Loss of Appetite Any 21 19.1 12.2 27.7 23 20.9 13.7 29.7 Grade 3 2 1.8 0.2 6.4 1 0.9 0.0 5.0 Related 19 17.3 10.7 25.7 23 20.9 13.7 29.7 Restlessness Any 58 52.7 43.0 62.3 52 47.3 37.7 57.0 Grade 3 2 1.8 0.2 6.4 2 1.8 0.2 6.4 Related 58 52.7 43.0 62.3 52 47.3 37.7 57.0 Fever (rectal) Any 9 8.2 3.8 15.0 12 10.9 5.8 18.3-8 -
Related 9 8.2 3.8 15.0 12 10.9 5.8 18.3 Unusual Crying Any 28 25.5 17.6 34.6 26 23.6 16.1 32.7 Grade 3 2 1.8 0.2 6.4 2 1.8 0.2 6.4 Related 28 25.5 17.6 34.6 26 23.6 16.1 32.7 Vomiting Any 14 12.7 7.1 20.4 6 5.5 2.0 11.5 Related 13 11.8 6.4 19.4 6 5.5 2.0 11.5 2 N 109 110 Diarrhoea Any 12 11.0 5.8 18.4 9 8.2 3.8 15.0 Related 11 10.1 5.1 17.3 9 8.2 3.8 15.0 Loss of Appetite Any 14 12.8 7.2 20.6 10 9.1 4.4 16.1 Grade 3 0 0.0 0.0 3.3 2 1.8 0.2 6.4 Related 13 11.9 6.5 19.5 10 9.1 4.4 16.1 Restlessness Any 47 43.1 33.7 53.0 40 36.4 27.4 46.1 Grade 3 0 0.0 0.0 3.3 4 3.6 1.0 9.0 Related 45 41.3 31.9 51.1 38 34.5 25.7 44.2 Fever (rectal) Any 9 8.3 3.8 15.1 9 8.2 3.8 15.0 Related 9 8.3 3.8 15.1 8 7.3 3.2 13.8 Unusual Crying Any 23 21.1 13.9 30.0 21 19.1 12.2 27.7 Grade 3 1 0.9 0.0 5.0 2 1.8 0.2 6.4 Related 22 20.2 13.1 28.9 21 19.1 12.2 27.7 Vomiting Any 8 7.3 3.2 14.0 9 8.2 3.8 15.0 Related 6 5.5 2.0 11.6 9 8.2 3.8 15.0 3 N 109 109 Diarrhoea Any 7 6.4 2.6 12.8 8 7.3 3.2 14.0 Grade 3 1 0.9 0.0 5.0 0 0.0 0.0 3.3 Related 5 4.6 1.5 10.4 7 6.4 2.6 12.8 Loss of Appetite Any 16 14.7 8.6 22.7 18 16.5 10.1 24.8 Related 15 13.8 7.9 21.7 17 15.6 9.4 23.8 Restlessness Any 34 31.2 22.7 40.8 39 35.8 26.8 45.5 Grade 3 2 1.8 0.2 6.5 1 0.9 0.0 5.0 Related 32 29.4 21.0 38.8 39 35.8 26.8 45.5 Fever (rectal) Any 3 2.8 0.6 7.8 11 10.1 5.1 17.3 Related 2 1.8 0.2 6.5 9 8.3 3.8 15.1 Unusual Crying Any 14 12.8 7.2 20.6 15 13.8 7.9 21.7 Grade 3 1 0.9 0.0 5.0 1 0.9 0.0 5.0 Related 14 12.8 7.2 20.6 15 13.8 7.9 21.7 Vomiting Any 6 5.5 2.0 11.6 7 6.4 2.6 12.8 Grade 3 0 0.0 0.0 3.3 1 0.9 0.0 5.0 Related 5 4.6 1.5 10.4 7 6.4 2.6 12.8 Across N 110 110 Doses Diarrhoea Any 29 26.4 18.4 35.6 24 21.8 14.5 30.7 Grade 3 1 0.9 0.0 5.0 0 0.0 0.0 3.3 Related 26 23.6 16.1 32.7 23 20.9 13.7 29.7 Loss of Appetite Any 37 33.6 24.9 43.3 36 32.7 24.1 42.3-9 -
Grade 3 2 1.8 0.2 6.4 3 2.7 0.6 7.8 Related 34 30.9 22.4 40.4 36 32.7 24.1 42.3 Restlessness Any 79 71.8 62.4 80.0 76 69.1 59.6 77.6 Grade 3 4 3.6 1.0 9.0 6 5.5 2.0 11.5 Related 78 70.9 61.5 79.2 75 68.2 58.6 76.7 Fever (rectal) Any 17 15.5 9.3 23.6 27 24.5 16.8 33.7 Related 16 14.5 8.5 22.5 25 22.7 15.3 31.7 Unusual Crying Any 48 43.6 34.2 53.4 44 40.0 30.8 49.8 Grade 3 3 2.7 0.6 7.8 5 4.5 1.5 10.3 Related 47 42.7 33.3 52.5 44 40.0 30.8 49.8 Vomiting Any 22 20.0 13.0 28.7 18 16.4 10.0 24.6 Grade 3 0 0.0 0.0 3.0 1 0.9 0.0 5.0 Related 19 17.3 10.7 25.7 18 16.4 10.0 24.6 n/% = number/percentage of subjects who reported a given symptom 95% CI, LL and UL = 95% confidence interval, upper and lower limits N = number of subjects with symptom sheets returned Any = incidence of a particular symptom regardless of grade or relationship to vaccinations Grade 3 = AE which prevented normal everyday activities. Related = a direct cause and effect relationship existed Fever = Any fever 38.0 C Grade 3 fever >39.5 C Safety Results: Number (%) of subjects with unsolicited Adverse Events after vaccination (ITT cohort) Incidence of 5 most frequent unsolicited adverse events in each group during the 30-day follow-up after each vaccine dose (ITT cohort) Most Frequent Adverse Events On-Therapy (Within Day 0-30 following vaccination) (ITT cohort) Group 1 N = 219 Group 2 Group 3 Group 4 Subjects with any AE(s), n (%) 182 (83.1) 86 (78.2) 88 (80.0) 86 (78.2) injection site reaction 83 (37.9) 34 (30.9) 41 (37.3) 44 (40.0) pharyngitis 73 (33.3) 25 (22.7) 27 (24.5) 37 (33.6) vitamin D deficiency 30 (13.7) 24 (21.8) 26 (23.6) 17 (15.5) infection viral 36 (16.4) 14 (12.7) 12 (10.9) 19 (17.3) upper respiratory tract infection 29 (13.2) 12 (10.9) 10 (9.1) 15 (13.6) nervousness 17 (7.8) 11 (10.0) 12 (10.9) 10 (9.1) bronchitis 21 (9.6) 12 (10.9) 5 (4.5) 10 (9.1) Safety Results: Number (%) of Serious Adverse Events (SAEs) [number of SAEs considered by the investigator to be related to study medication] (ITT cohort) Serious Adverse Events - On-Therapy (over the study) Group 1 N = 219 Group 2 Group 3 Group 4 Subjects with any SAE(s) n (%) [related] 11 (5.0) [0] 2 (1.8) [1] 4 (3.6) [0] 9 (8.2) [0] anemia 3 (1.4) [0] 0 (0.0) [0] 1 (0.9) [0] 0 (0.0) [0] anemia hypochromic 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0] 1 (0.9) [0] bronchitis 1 (0.5) [0] 1 (0.9) [0] 1 (0.9) [0] 1 (0.9) [0] colitis 1 (0.5) [0] 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0] conjunctivitis 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0] 1 (0.9) [0] convulsions 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0] 2 (1.8) [0] dehydration 1 (0.5) [0] 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0] dermatitis 1 (0.5) [0] 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0] dyspnea 4 (1.8) [0] 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0] edema genital 1 (0.5) [0] 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0] enteritis 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0] 1 (0.9) [0] enterocolitis 0 (0.0) [0] 1 (0.9) [0] 0 (0.0) [0] 0 (0.0) [0] - 10 -
fever 0 (0.0) [0] 1 (0.9) [1] 0 (0.0) [0] 0 (0.0) [0] furunculosis 0 (0.0) [0] 0 (0.0) [0] 1 (0.9) [0] 0 (0.0) [0] gastroenteritis 2 (0.9) [0] 0 (0.0) [0] 0 (0.0) [0] 1 (0.9) [0] infection bacterial 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0] 1 (0.9) [0] infection viral 3 (1.4) [0] 2 (1.8) [0] 2 (1.8) [0] 3 (2.7) [0] injury 1 (0.5) [0] 0 (0.0) [0] 0 (0.0) [0] 1 (0.9) [0] laryngitis 1 (0.5) [0] 0 (0.0) [0] 0 (0.0) [0] 1 (0.9) [0] neuropathy 1 (0.5) [0] 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0] otitis media 1 (0.5) [0] 0 (0.0) [0] 1 (0.9) [0] 1 (0.9) [0] pharyngitis 4 (1.8) [0] 0 (0.0) [0] 1 (0.9) [0] 3 (2.7) [0] pneumonia 4 (1.8) [0] 0 (0.0) [0] 2 (1.8) [0] 1 (0.9) [0] respiratory disorder 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0] 1 (0.9) [0] respiratory insufficiency 3 (1.4) [0] 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0] rhinitis 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0] 1 (0.9) [0] syncope 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0] 1 (0.9) [0] upper respiratory tract infection 0 (0.0) [0] 1 (0.9) [0] 0 (0.0) [0] 1 (0.9) [0] vitamin D deficiency 1 (0.5) [0] 1 (0.9) [0] 0 (0.0) [0] 3 (2.7) [0] Fatal Serious Adverse Events On therapy (over the study) Group 1 N = 219 Group 2 Group 3 Group 4 Subjects with fatal SAE(s) n (%) [related] 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0] Conclusion: See publication below. Publications: Usonis V, Bakasenas V. Does concomitant injection of a combined diphtheria-tetanus-acellular pertussis-hepatatis B virus-inactivated polio virus vaccine influence the reactogenicity and immunogenicity of commercial Haemophilus influenzae type B conjugate vaccines? EUR J PEDIATR.1999; 158(5):398-402. Date Updated: 09-Jun-2005-11 -