Study No.: Title: Rationale: Phase: Study Period: Study Design: Centres: Indication: Treatment: Study vaccines Objectives:

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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.: /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 -

2 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 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) 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 PIII Pre PIII Pre PIII Pre PIII

3 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 PIII Pre PIII Pre PIII Pre PIII 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 S Total S S Total S S Total S S Total Anti-FHA 1 S S Total S S Total S S Total S S Total Anti-PRN 1 S S Total S S Total

4 3 S S Total S S Total 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 PIII Pre PIII Pre PIII Pre PIII Anti-FHA 1 Pre PIII Pre PIII Pre PIII Pre PIII Anti-PRN 1 Pre PIII Pre PIII Pre PIII Pre PIII 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 PIII Pre PIII Pre PIII

5 4 Pre PIII 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 type 1 2 PIII PIII PIII Anti-poliovirus 1 PIII type 2 2 PIII PIII PIII Anti-poliovirus 1 PIII type 3 2 PIII PIII PIII 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 PIII Pre PIII Pre PIII Pre PIII 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 Pain Any Grade Redness Any Grade

6 Swelling Any Grade N Pain Any Grade Redness Any Grade Swelling Any Grade N Pain Any Grade Redness Any Grade Swelling Any Grade Across N Doses Pain Any Grade Redness Any Grade Swelling Any Grade Group 3 Group 4 95% CI 95% CI Dose Symptom n % LL UL n % LL UL 1 N Pain Any Redness Any Grade Swelling Any Grade N Pain Any Redness Any Grade Swelling Any Grade N Pain Any Redness Any Grade Swelling Any Grade Across N Doses Pain Any

7 Redness Any Grade Swelling Any Grade 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 Diarrhoea Any Grade Related Loss of Appetite Any Grade Related Restlessness Any Grade Related Fever (rectal) Any Grade Related Unusual Crying Any Grade Related Vomiting Any Grade Related N Diarrhoea Any Grade Related Loss of Appetite Any Grade Related Restlessness Any Grade Related Fever (rectal) Any Grade Related Unusual Crying Any Grade Related Vomiting Any Grade Related N Diarrhoea Any Grade

8 Related Loss of Appetite Any Grade Related Restlessness Any Grade Related Fever (rectal) Any Grade Related Unusual Crying Any Grade Related Vomiting Any Grade Related Across N Doses Diarrhoea Any Grade Related Loss of Appetite Any Grade Related Restlessness Any Grade Related Fever (rectal) Any Grade Related Unusual Crying Any Grade Related Vomiting Any Grade Related Group 3 Group 4 95% CI 95% CI Dose Symptom n % LL UL n % LL UL 1 N Diarrhoea Any Related Loss of Appetite Any Grade Related Restlessness Any Grade Related Fever (rectal) Any

9 Related Unusual Crying Any Grade Related Vomiting Any Related N Diarrhoea Any Related Loss of Appetite Any Grade Related Restlessness Any Grade Related Fever (rectal) Any Related Unusual Crying Any Grade Related Vomiting Any Related N Diarrhoea Any Grade Related Loss of Appetite Any Related Restlessness Any Grade Related Fever (rectal) Any Related Unusual Crying Any Grade Related Vomiting Any Grade Related Across N Doses Diarrhoea Any Grade Related Loss of Appetite Any

10 Grade Related Restlessness Any Grade Related Fever (rectal) Any Related Unusual Crying Any Grade Related Vomiting Any Grade Related 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]

11 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): Date Updated: 09-Jun