Study No.: Title: Rationale: Phase: Study Period: Study Design: Centres: Indication: Treatment: Objectives: Primary Outcome/Efficacy Variable:

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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.: /030 (DTPa-HBV-IPV-030) Title: A phase III open randomised primary vaccination study of three doses of SB Biologicals DTPa-HBV-IPV vaccine co-administered with SB Biologicals Hib vaccine into opposite limbs, compared to commercially available DTPw-IPV/Hib vaccine co-administered with hepatitis B vaccine, in healthy children Rationale: To compare the co-administration of DTPa-HBV-IPV and Haemophilus influenzae type b (Hib) vaccines to a commercially available combined DTPw-IPV/Hib vaccine. DTPa = diphtheria, tetanus, acellular pertussis; DTPw = diphtheria, tetanus, whole-cell pertussis; HBV = hepatitis B vaccine; IPV = inactivated polio vaccine; Hib = haemophilus influenzae type b conjugate vaccine (Hib) Phase: III Study Period: 20 November 1997 to 2 July 1998 Study Design: Open randomised study with two balanced groups. Centres: One centre in the Republic of Moldova Indication: Primary vaccination of healthy infants aged 6 weeks at enrolment, previously primed with one dose of hepatitis B vaccine at birth Treatment: Study groups were as follows: -Group 1: DTPa-HBV-IPV vaccine given concomitantly in a separate injection with Hib vaccine at 6, 10 and 14 weeks of age -Group 2: DTPw-IPV/Hib given concomitantly in a separate injection with Hepatitis B vaccine (HBV) at 6, 10 and 14 weeks of age. All vaccines were to be administered by deep intramuscular injection. Combined DTPa-HBV-IPV and DTPw-IPV/Hib vaccines in the right thigh and Hib and HBV vaccines in the left thigh. Objectives: The primary objective was to evaluate whether DTPa-HBV-IPV co-administered with Hib vaccine was not significantly less immunogenic than DTPw-IPV/Hib vaccine co-administered with hepatitis B vaccine. Primary Outcome/Efficacy Variable: One month after the administration of the third dose of the study vaccines: Percentage of subjects with antibody to Hepatitis B surface antigen (Anti-HBs) 10 miu/ml Percentage of subjects with antibody to Diphtheria antigen (Anti-D) 0.1 IU/ml Percentage of subjects with antibody to Tetanus antigen (Anti-T) 0.1 IU/ml Percentage of subjects with Anti-polio type 1 titres 8 Percentage of subjects with Anti-polio type 2 titres 8 Percentage of subjects with Anti-polio type 3 titres 8 Vaccine response to anti-pertussis toxoid (PT), anti-filamentous hemagglutinin (FHA) and anti-pertactin (PRN) (vaccine response is defined as the appearance of antibodies in subjects who are initially seronegative, and at least maintenance of pre-vaccination antibody titres in those who are initially seropositive) Anti-PT, anti-fha and anti-prn antibody concentrations Secondary Outcome/Efficacy Variable(s): Percentage of subjects with anti-polyribosyl-ribitol-phosphate (PRP) 0.15 µg/ml and 1.0 µg/ml Anti-D, anti-t, anti-hbs, anti-polio type 1, 2 & 3 and anti-prp antibody concentrations or titres. Incidence of solicited symptoms during the 4-day (day0-day3) follow up period after vaccination Incidence of unsolicited adverse events during the 31-day (day 0-day30) follow up period after vaccination Incidence of Serious Adverse Events (SAEs) occurring at any time throughout the study period Statistical Methods: The analyses were performed on the According-To-Protocol (ATP) cohort for immunogenicity and the ATP cohort for safety. -The ITT cohort included all enrolled subjects. -The ATP cohort for immunogenicity included all evaluable subjects (i.e., those meeting all inclusion/exclusion criteria and complying with the procedures defined in the protocol) for whom assay results were available for antibodies against at least one study vaccine antigen component. 1

2 -The ATP cohort for safety included all subjects who had received at least one dose of study vaccine according to their random assignment, with sufficient data to perform an analysis of safety and who had not received a vaccine not specified or forbidden in the protocol. Analysis of Immunogenicity : The primary analysis of immunogenicity was performed on the ATP cohort for immunogenicity. Exact 90% confidence intervals (CIs) for the differences in the seroprotection rates and vaccine response rates were calculated for each group. The 90%CIs for the Geometric Mean Titres/Concentrations (GMT/GMC) ratios were derived from a one-way ANOVA model on the logarithm of the titers/concentrations. The primary objective was reached if the upper limits of the 90% CIs for the difference between groups in were below 10% and if the upper limits of the 90% CI for the GMC ratios for pertussis components (group 2/ group 1) were below 1.5. For each treatment group, the seropositivity, seroprotection and vaccine response rates one month after the third dose and their exact 95% CIs were calculated and the antibody titres/concentrations were summarized by GMTs/GMCs and their 95% CIs. Analysis of Safety: The primary analyses of safety were based on the ATP cohort for safety. The percentage of subjects reporting solicited local and general symptoms within the 4 days following each vaccine dose and their exact 95% confidence interval (CI) were computed by vaccine group according to the type of symptoms, their intensity and their relationship to vaccination. The percentage of subjects reporting unsolicited symptoms within 31 days (day 0-day 30) following each vaccine dose was summarized by vaccine group according to the WHO preferred term Study Population: Healthy infants aged 6 weeks at enrolment, previously primed with one dose of hepatitis B vaccine at birth, all of whom qualified based on the inclusion and exclusion criteria after screening results were available. The subjects were 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 all subjects prior to study entry. Number of Subjects: Group 1 Group 2 (ITT Cohort) Planned, N Randomised, N Completed, n (%) 157 (98.1) 155 (96.9) Total Number Subjects Withdrawn, n (%) 3 (1.9) 5 (3.1) Withdrawn due to Adverse Events n (%) 0 (0.0) 0 (0.0) Withdrawn due to Lack of Efficacy n (%) not applicable not applicable Withdrawn for other reasons n (%) 3 (1.9) 5 (3.1) Demographics Group Group 1 Group 2 N (ITT cohort) Females: Males 71:89 87:73 Mean Age, weeks(sd) 6.4 (0.86) 6.4 (0.95) White, n (%) 157 (98.1) 160 (100.0) Primary Efficacy Results: Difference between groups in seroprotection/vaccine response rates one month after the third vaccine dose (ATP cohort for immunogenicity). Endpoint Group 1 Group 2 Group 2 minus Group 1 N Rate (%) N Rate (%) Difference in Rates (%) 90% CI LL UL Vaccine response to PT * Vaccine response to FHA * Vaccine response to PRN Anti-D 0.1 IU/ml * Anti-T 0.1 IU/ml * Anti-Polio * Anti-Polio * Anti-Polio * Anti-HBs 10 miu/ml * N = number of subjects with available results (for vaccine response, with both pre-and post-vaccination results) 90% CI, LL and UL = 90% Exact confidence interval, lower and upper limit 2

3 * upper limit of 90% CI below the 10% clinical limit for non-inferiority Vaccine response: appearance of detectable antibodies (i.e. concentration cut-off 5 EL.U/ml) in subjects initially seronegative or at least maintenance of pre-vaccination antibody concentrations in those initially seropositive. Primary Efficacy Results: GMC ratios and 90% CIs for anti-pt, anti-fha and anti-prn antibodies one month after the third vaccine dose (ATP cohort for immunogenicity) Endpoint Group 1 Group 2 Group 2/Group 1 N GMC N GMC GMC Ratio 90% CI Anti-PT * Anti-FHA * Anti-PRN * N = number of subjects with available results 90% CI, LL and UL = 90% confidence interval, lower and upper limit * 90% CI upper limit below the clinical limit for non inferiority (1.5) Seroprotection rates and GMCs for anti-prp antibodies ( ATP cohort for immunogenicity) Group Timing N 0.15 µg/ml 1.0 µg/ml GMC n % 95%CI n % 95%CI µg/ml 95%CI 1 Pre ; ; ; PII(m2) ; ; ; PIII(m3) ; ; ; Pre ; ; ; PII(m2) ; ; ; PIII(m3) ; ; ; N =Total number of subjects with available results n/%= number /percentage of subjects with titres within the specified range 95%CI= 95% confidence intervals, lower and upper limit Pre: immediately before the first dose PII(m2): post vaccination blood sample obtained one month after the second dose PIII(m3): approximately one month after the third dose Seroprotection rates (anti-diphtheria and anti-tetanus antibody titres 0.1 IU/ml) and GMCs of anti-diphtheria and antitetanus antibody concentrations (ATP cohort for immunogenicity) Antibody Group Timing 0.1 IU/ml GMC N n % 95% CI (IU/ml) 95% CI Anti- diphtheria 1 Pre ; ; PII(m2) ; ; PIII(m3) ; ; Pre ; ; PII(m2) ; ; PIII(m3) ; ; Anti-tetanus 1 Pre ; ; PII(m2) ; ; PIII(m3) ; ; Pre ; ; PII(m2) ; ; PIII(m3) ; ; N = number of subjects with available results n/%= number /percentage of subjects with titres within the specified range 95% CI = 95% confidence interval Pre: pre-vaccination blood sample obtained at the time of first vaccine dose PII(m2): post vaccination blood sample obtained one month after the second dose PIII(m3): post vaccination blood sample obtained one month after the third dose Seroprotection rates and GMCs of anti-hbs antibody ( ATP cohort for immunogenicity) 3

4 Group Timing N 10mIU/ml GMC n % 95%CI (miu/ml) 95%CI 1 Pre ; ; 30.1 PII(m2) ; ; PIII(m3) ; ; Pre ; ; 20.3 PII(m2) ; ; PIII(m3) ; ; N = number of subjects with available results n/% = number/ percentage of subjects with concentrations within the specified range 95% CI = 95% confidence interval Pre: pre-vaccination blood sample obtained at the time of first vaccine dose PII(m2): post vaccination blood sample obtained one month after the second dose PIII(m3): post vaccination blood sample obtained one month after the third dose Seroprotection and GMTs of anti-polio 1, anti-polio 2, anti-polio 3 antibodies ( ATP cohort for immunogenicity) Antibody Group Timing N 8 GMT n % 95%CI Value 95%CI Anti-polio 1 1 Pre ; ; 25.3 PII(m2) ; ; PIII(m3) ; ; Pre ; ; 27.4 PII(m2) ; ; 81.6 PIII(m3) ; ; Anti-polio 2 1 Pre ; ; 24.7 PII(m2) ; ; 53.4 PIII(m3) ; ; Pre ; ; 19.9 PII(m2) ; ; 37.3 PIII(m3) ; ; Anti-polio 3 1 Pre ; ; 6.7 PII(m2) ; ; PIII(m3) ; ; Pre ; ; 6.6 PII(m2) ; ; PIII(m3) ; ; N = number of subjects with available results n/% = number of subjects with titres within the specified range 95% CI = 95% confidence interval Pre: pre-vaccination blood sample obtained at the time of first vaccine dose PII(m2): post vaccination blood sample obtained one month after the second dose PIII(m3): post vaccination blood sample obtained one month after the third dose Percentage of subjects who reported at least one solicited symptom during the 4-day (day0-day3) follow-up period (ATP cohort for safety) Group 1 Group 2 95% CI 95% CI Symptom n % LL UL n % LL UL Dose 1 N=160 N=160 Pain Any Grade Redness Any Grade Swelling Any Grade Dose 2 N=158 N=156 4

5 Pain Any Grade Redness Any Grade Swelling Any Grade Dose 3 N=157 N=156 Pain Any Grade Redness Any Grade Swelling Any Grade Across doses N=160 N=160 Pain Any Grade Redness Any Grade Swelling Any Grade n = number of subjects who reported a given symptom N = number of subjects with symptom sheets returned 95% CI = 95% confidence interval; LL and UL = lower and upper limit Any = incidence of a particular symptom regardless of grade or relationship to vaccinations Grade 3 Pain = cried when limb was moved/spontaneously painful Grade 3 Redness = redness >20 mm Grade 3 Swelling = swelling >20 mm Incidence of solicited general symptoms after any vaccine dose during the 4-day (day0-day3) follow-up period ( ATP cohort for safety) Group 1 Group 2 95% CI 95% CI Symptom N % LL UL n % LL UL Dose 1 N=160 N=160 Diarrhoea Any Grade Related Loss of appetite Any Grade Related Restlessness Any Grade Related Fever (rectal) Grade Related Vomiting Any Grade Related Fussiness Any Grade Related Sleeping more than usual Any Grade

6 Related Dose 2 N= 158 N= 156 Diarrhoea Any Grade Related Loss of appetite Any Grade Related Restlessness Any Grade Related Fever (rectal) Grade Related Vomiting Any Grade Related Fussiness Any Grade Related Sleeping more than usual Any Grade Related Dose 3 N= 157 N= 156 Diarrhoea Any Grade Related Loss of appetite Any Grade Related Restlessness Any Grade Related Fever (rectal) Grade Related Vomiting Any Grade Related Fussiness Any Grade Related Sleeping more than usual Any Grade Related Across doses N= 160 N=160 Diarrhoea Any Grade Related Loss of appetite Any

7 Grade Related Restlessness Any Grade Related Fever (rectal) Grade Related Vomiting Any Grade Related Fussiness Any Grade Related Sleeping more than usual Any Grade Related n = number of subjects who reported a given symptom N = number of subjects with symptom sheets returned 95% CI = 95% confidence interval; LL and UL = lower and upper limit Any = incidence of a particular symptom regardless of grade or relationship to vaccinations Grade 3 for all symptoms except fever = one particular symptom preventing normal everyday activities. fever (rectal) grade 3 >39.5 C (>103 F) Related = a direct cause and effect relationship existed Safety Results: Number (%) of subjects with unsolicited Adverse Events (ATP cohort for safety) Most frequent adverse events On-Therapy- (occurring within day0-day30 following vaccination) Group 1 Group 2 Subjects with any AE(s), n(%) 9 (5.6) 20 (12.5) enteritis 1 (0.6) 4 (2.5) injection site reaction 1 (0.6) 4 (2.5) upper respiratory tract infection 2 (1.3) 3 (1.9) dermatitis 2 (1.3) 1 (0.6) agitation 1 (0.6) 1 (0.6) diarrhea 1 (0.6) 1 (0.6) rhinitis 0 (0.0) 2 (1.3) coughing 0 (0.0) 1 (0.6) face edema 1 (0.6) 0 (0.0) hypertonia 0 (0.0) 1 (0.6) infection bacterial 0 (0.0) 1 (0.6) injury 0 (0.0) 1 (0.6) pharyngitis 0 (0.0) 1 (0.6) pneumonia 0 (0.0) 1 (0.6) urticaria 0 (0.0) 1 (0.6) Safety Results: Number (%) of Serious Adverse Events (SAEs) (ITT cohort) All SAEs Group 1 Group 2 Subjects with any SAE(s), n (%) [related] 0 (0.0) [0] 0 (0.0) [0] Fatal SAEs Group 1 Group 2 Subjects with fatal SAE(s), n (%) [n related] 0 (0.0) [0] 0 (0.0) [0] 7

8 Conclusion: See publication below. Publications: Gylca R, et al. A new DTPa-HBV-IPV vaccine co-administered with Hib, compared to commercially available DTPw-IPV/Hib vaccine co-administered with HBV, given at 6, 10 and 14 weeks following HBV at birth. VACCINE. 2000;19(7-8): Date Updated: 21-Jun

Study No.: Title: Rationale: Phase: Study Period: Study Design: Centres: Indication Treatment: Objectives: Primary Outcome/Efficacy Variable:

Study No.: Title: Rationale: Phase: Study Period: Study Design: Centres: Indication Treatment: Objectives: Primary Outcome/Efficacy Variable: 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.