Study No.: Title: Rationale: Phase: Study Period: Study Design: Centers: 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.: /015 (Malaria-015) & /022 (EXT Malaria-015) Title: A phase I, double-blind, randomized, controlled, staggered study to evaluate the safety, reactogenicity and immunogenicity of 1/5 th, ½, and full doses of GlaxoSmithKline Biologicals RTS,S/AS02 candidate malaria vaccine, administered intramuscularly according to a 0,1,3-month vaccination schedule in semi-immune children aged 6 to 11 years in The Gambia, a malaria endemic region. RTS,S/AS02D (RTS,S): GlaxoSmithKline (GSK) Biologicals candidate Plasmodium falciparum malaria vaccine. Rationale: The purpose of the primary study was to evaluate the safety and immunogenicity of different formulations of RTS,S vaccine when administered in a staggered fashion, spaced at 10-day intervals in in semi-immune (i.e. malariaexperienced) children aged 6 to 11 years. A licensed rabies vaccine was used as a control. The purpose of the long-term follow-up study was to monitor the safety and persistence of immune response over 1 year in the children who participated in the primary study. Rab: Aventis Pasteur s rabies vaccine. Phase: I Study Period: /15: 04 April 2001 to 12 October 2001 (primary study), 1 March 2002 (safety follow-up end-date) /022: 15 June 2002 to 18 March 2003 Study Design: The primary study was a double-blind, randomized, controlled, staggered study with 6 groups. Centers: 1 center in Gambia. Indication: Immunization against malaria and rabies of children aged 6 to 11 years. Treatment: The study groups were as follows: RTS,S 0.1 Group : Subjects received 3 doses of RTS,S vaccine (0.1mL) on Days 0, 30 and 90. RTS,S 0.25 Group : Subjects received 3 doses of RTS,S vaccine (0.25mL) on Days 0, 30 and 90. RTS,S 0.5 Group : Subjects received 3 doses of RTS,S vaccine (0.5mL) on Days 0, 30 and 90. Control 1 Group : Subjects received 3 doses of Rab vaccine on Days 0, 30 and 90. Control 2 Group : Subjects received 3 doses of Rab vaccine on Days 0, 30 and 90. Control 3 Group : Subjects received 3 doses of Rab vaccine on Days 0, 30 and 90. Vaccines were administered intramuscularly in the deltoid region of alternating arms. Note: To allow the Data Safety Monitoring Committee to review safety data before approving vaccination at the next higher dose level, vaccination was performed in a staggered fashion spaced at 10-day intervals, i.e. subjects in the RTS,S 0.1 Group were vaccinated 10 calendar days before subjects in the RTS,S 0.25 Group, and subjects in the RTS,S 0.25 Group were vaccinated 10 calendar days before subjects in the RTS,S 0. 5 Group. For each group treated with a fraction of the RTS,S vaccine a corresponding control group receiving the Rab vaccine was created. Objectives: Primary study: To evaluate the safety of the candidate RTS,S vaccine in children 6 through 11 years of age in The Gambia. Long-term follow-up study: To monitor the safety and immunogenicity in children who previously participated in the primary study. Primary Outcome/Efficacy Variable: Primary Study: Occurrence of solicited symptoms after each vaccination over a 4-day follow-up period (day of vaccination and 3 subsequent days). Occurrence of unsolicited symptoms after each vaccination over a 30-day follow-up period (day of vaccination and 29 subsequent days). Occurrence of serious adverse events (SAEs) throughout the study period (up to Month 9, Day 270) Long-term follow-up Occurrence of SAEs during the study period* (i.e. between Month 13 and Month 21 post-dose 1). * Any SAEs occurring since last visit of primary study at Month 4 up to Month 21 were reported Secondary Outcome/Efficacy Variable(s): Primary Study: Titers of circumsporozoite (CS) antibody at each time point where serology samples were analyzed (Screening,

2 Days 60, 90 and 104). Titers of hepatitis-b (HBs) antibody at time points where serology samples were analyzed (Screening, Days 60, 90 and 104). Long-term follow-up Anti-CS antibodies at the time points for which serology samples were analyzed (Month 13 and 19) Statistical Methods: The analyses were performed on the Total cohort, the According to Protocol (ATP) cohort for immunogenicity and the Longterm ATP cohort for immunogenicity. - The Total cohort included all enrolled (i.e. randomized and vaccinated) subjects for whom data were available. - The ATP cohort for immunogenicity included all evaluable subjects (i.e., those meeting all eligibility criteria, complying with the procedures defined in the protocol) who had received all 3 doses according to protocol and who had data available at all time points when immunogenicity measurements were performed. - The Long-term ATP cohort for immunogenicity included all evaluable vaccinated subjects from the primary study (i.e. those meeting all eligibility criteria, complying with the procedures defined in the protocol, and fulfilling requirements for analysis) for whom immunogenicity data were available. This excluded subjects who did not comply with the protocol of /15. Primary study Analysis of safety The analysis was performed on the Total cohort. The percentage of subjects reporting solicited local and general symptoms over a 4-day follow-up period after each vaccination was calculated with exact 95% confidence interval (CI). The same calculations were performed for grade 3 symptoms and for general symptoms assessed by the investigator as related to vaccination. The proportion of subjects reporting unsolicited adverse events (AEs) over a 30-day follow-up period after each vaccination was tabulated according to World Health Organization (WHO) Dictionary for Adverse Reaction Terminology (WHOART) preferred terms. SAEs were collected and summarized throughout the primary study (up to Month 9) by WHO preferred term. Analysis of immunogenicity The analysis was performed on the ATP cohort for immunogenicity. At each time point when serology samples were analyzed, seropositivity rates and Geometric Mean Concentrations (GMC) for anti-cs antibodies and HBs antibodies were calculated with 95% CI for all the treatment groups and control groups. Long-term follow-up study Analysis of safety The analysis was performed on the Total cohort. SAEs occurring since last visit of primary study at Month 4 up to Month 21 post-dose 1 were tabulated according to the WHO preferred terms. Analysis of immunogenicity The analysis was performed on the Long-term ATP cohort for immunogenicity. At months 13 and 19, seropositivity rates and GMCs for anti-cs antibodies were calculated with 95% CI for all the treatment groups and control groups. Study Population: Healthy male or female subjects between, and including, 6 and 11 years of age at the time of the first vaccination. Written informed consent from the subject s parents or guardians and oral assent from the subject were obtained. Primary study RTS, S Groups Number of Subjects: RTS,S 0.1 Group RTS,S 0.25 Group RTS,S 0.5 Group Planned, N Randomized, N (Total cohort) Completed, n (%) 19 (95.0) 18 (90.0) 20 (100) Total Number Subjects Withdrawn, n (%) 1 (5.0) 2 (10.0) 0 (0.0) Withdrawn due to Adverse Events n (%) 0 (0.0) 0 (0.0) 0 (0.0) Withdrawn due to Lack of Efficacy n (%) Not Applicable Not Applicable Not Applicable Withdrawn for other reasons n (%) 1 (5.0) 2 (10.0) 0 (0.0) Demographics RTS,S 0.1 Group RTS,S 0.25 Group RTS,S 0.5 Group N, (Total cohort)

3 Females: Males 10:10 9:11 7:13 Mean Age, years (SD) 8.0 (1.39) 8.0 (1.39) 8.0 (1.49) Race, n (%) Not Available Not Available Not Available Control Groups Number of Subjects: Control 1 Group Control 2 Group Control 3 Group Planned, N Randomized, N (Total cohort) Completed, n (%) 10 (100) 9 (90.0) 9 (90.0) Total Number Subjects Withdrawn, n (%) 0 (0.0) 1 (10.0) 1 (10.0) Withdrawn due to Adverse Events n (%) 0 (0.0) 0 (0.0) 0 (0.0) Withdrawn due to Lack of Efficacy n (%) Not Applicable Not Applicable Not Applicable Withdrawn for other reasons n (%) 0 (0.0) 1 (10.0) 1 (10.0) Demographics Control 1 Group Control 2 Group Control 3 Group N, (Total cohort) Females: Males 5:5 4:6 6:4 Mean Age, years (SD) 8.0 (1.56) 7.9 (1.52) 8.3 (1.42) Race, n (%) Not Available Not Available Not Available Long term follow-up study RTS, S Groups Number of Subjects: RTS,S 0.1 Group RTS,S 0.25 Group RTS,S 0.5 Group Planned in the primary study, N Entered, N (Total cohort) Completed, n (%) 17 (100) 16 (94.1) 18 (94.7) Total Number Subjects Withdrawn, n (%) 0 (0.0) 1 (5.9) 1 (5.3) Withdrawn due to Adverse Events n (%) 0 (0.0) 0 (0.0) 0 (0.0) Withdrawn due to Lack of Efficacy n (%) Not Applicable Not Applicable Not Applicable Withdrawn for other reasons n (%) 0 (0.0) 1 (5.9) 1 (5.3) Demographics RTS,S 0.1 Group RTS,S 0.25 Group RTS,S 0.5 Group N, (Total cohort) Females: Males 7:10 7:10 7:12 Mean Age, years (SD) 9.4 (1.46) 9.3 (1.96) 9.2 (1.47) Race, n (%) Not Available Not Available Not Available Control Groups Number of Subjects: Control 1 Group Control 2 Group Control 3 Group Planned, N Entered, N (Total cohort) Completed, n (%) 9 (90.0) 10 (100) 9 (100) Total Number Subjects Withdrawn, n (%) 1 (10.0) 0 (0.0) 0 (0.0) Withdrawn due to Adverse Events n (%) 0 (0.0) 0 (0.0) 0 (0.0) Withdrawn due to Lack of Efficacy n (%) Not Applicable Not Applicable Not Applicable Withdrawn for other reasons n (%) 1 (10.0) 0 (0.0) 0 (0.0) Demographics Control 1 Group Control 2 Group Control 3 Group N, (Total cohort) Females: Males 5:5 4:6 6:3 Mean Age, years (SD) 9.3 (1.64) 9.1 (1.60) 9.2 (1.48) Race, n (%) Not Available Not Available Not Available Primary Efficacy Results: Occurrence of solicited local symptoms during the 4-day follow-up period after each vaccination (Days 0-3) (Total cohort) Symptom Intensity RTS,S 0.1 Group Control 1 Group RTS,S 0.25 Group n % 95% CI n % 95% CI n % 95% CI LL UL LL UL LL UL Dose 1 Limited arm motion Any Grade

4 Pain Any Grade Swelling Any Grade Dose 2 Limited arm Any motion Pain Any Swelling Any Grade Dose 3 Limited arm Any motion Grade Pain Any Grade Swelling Any Grade Across Doses Limited arm Any motion Grade Pain Any Grade Swelling Any Grade Symptom Intensity Control 2 Group RTS,S 0.5 Group Control 3 Group n % 95% CI n % 95% CI n % 95% CI LL UL LL UL LL UL Dose 1 Limited arm Any motion Grade Pain Any Grade Swelling Any Grade Dose 2 Limited arm Any motion Pain Any Swelling Any Dose 3 N Limited arm Any motion Grade Pain Any Grade Swelling Any Grade

5 Across Doses Limited arm Any motion Grade Pain Any Grade Swelling Any Grade N = number of subjects with at least one documented dose n/% = number/percentage of subjects with at least one type of symptom 95% CI = exact 95% confidence interval; LL = Lower Limit; UL = Upper Limit. Any = any solicited local symptom regardless of intensity grade Grade 3 limited arm motion = abduction at the shoulder 30 Grade 3 pain = spontaneously painful Grade 3 swelling = swelling > 50 mm and persisting more than 24 hours Primary Efficacy Results: Incidence of solicited general symptoms during the 4-day follow-up period after each vaccination (Days 0-3) (Total cohort) Symptom Intensity/ Relationship RTS,S 0.1 Group Control 1 Group RTS,S 0.25 Group n % 95% CI n % 95% CI n % 95% CI LL UL LL UL LL UL Dose 1 Headache Any Related Malaise Any Related Nausea Any Related C >39.0 C Related Dose 2 Headache Any Related Malaise Any Related Nausea Any Related C >39.0 C Related Dose 3 N Headache Any Grade Related Malaise Any Grade

6 Related Nausea Any Grade Related C >39.0 C Related Across Doses Headache Any Related Malaise Any Related Nausea Any Related Symptom 37.5 C >39.0 C Related Intensity/ Relationship Control 2 Group RTS,S 0.5 Group Control 3 Group n % 95% CI n % 95% CI n % 95% CI LL UL LL UL LL UL Dose 1 N Headache Any Related Malaise Any Grade Related Nausea Any Related C >39.0 C Related Dose 2 Headache Any Related Malaise Any Related Nausea Any Related C >39.0 C Related Dose 3 N Headache Any

7 Grade Related Malaise Any Related Nausea Any Related C >39.0 C Related Across Doses Headache Any Grade Related Malaise Any Grade Related Nausea Any Related C >39.0 C Related N = number of subjects with at least one documented dose n/% = number/percentage of subjects with at least one type of symptom 95% CI = exact 95% confidence interval; LL = Lower Limit; UL = Upper Limit Any = any solicited symptom regardless of intensity grade Grade 3 symptoms = general symptoms that prevented normal activity Related = symptoms assessed by the investigator as causally related to vaccination Primary Efficacy Results: For results on unsolicited AEs and SAEs, please refer to the safety section of this document. Secondary Outcome Variable(s): Seropositivity rates and GMCs for anti-cs antibodies (ATP cohort for immunogenicity) Group Timing N S+ % 95% CI GMC 95% CI LL UL (µg/ml) LL UL RTS,S 0.1 Pre PII(D60) PII(D90) PIII(D104) Control 1 Pre PII(D60) PII(D90) PIII(D104) RTS,S 0.25 Pre PII(D60) PII(D90) PIII(D104) Control 2 Pre PII(D60) PII(D90) PIII(D104) RTS,S 0.5 Pre PII(D60) PII(D90) PIII(D104)

8 Control 3 Pre PII(D60) PII(D90) PIII(D104) Pooled controls Pre PII(D60) PII(D90) PIII(D104) N = number of subjects with available data S+ = number of subjects with concentrations > 1 µg/ml 95% CI = 95% confidence interval; LL = Lower Limit; UL = Upper Limit GMC = geometric mean antibody concentrations Pre = pre-vaccination (Screening) PII(D60) = post Dose 2 Day 60 PII(D90) = post Dose 2 Day 90 PIII(D104) = post Dose 3 Day 104 Secondary Outcome Variable(s): Seropositivity rates, seroprotection rates and GMCs of anti-hbs antibodies (ATP cohort for immunogenicity) Group Timing N S+ % 95% CI SP % 95% CI GMC 95% CI LL UL LL UL (miu/ml) LL UL RTS,S 0.1 Pre PII(D60) PII(D90) PIII(D104) Control 1 Pre PII(D60) PII(D90) PIII(D104) RTS,S 0.25 Pre PII(D60) PII(D90) PIII(D104) Control 2 Pre PII(D60) PII(D90) PIII(D104) RTS,S 0.5 Pre PII(D60) PII(D90) PIII(D104) Control 3 Pre PII(D60) E9* PII(D90) PIII(D104) Pooled controls Pre PII(D60) PII(D90) PIII(D104) N = number of subjects with available data S+ = seropositivity, number of subjects with concentrations 3.3 miu/ml SP = seroprotection, number of subjects with concentrations 10 miu/ml 95% CI = 95% confidence interval; LL = Lower Limit; UL = Upper Limit GMC = geometric mean antibody concentrations Pre = pre-vaccination (Screening) PII(D60) = post Dose 2 (Day 60) PII(D90) = post Dose 2 (Day 90)

9 PIII(D104) = post Dose 3 (Day 104) *1.034 x 10 9 miu/ml. Secondary Outcome Variable(s): Seropositivity rates and GMCs for anti-cs antibody concentrations (Long-term ATP cohort for immunogenicity) Group Timing N 1 µg/ml GMC (µg/ml) n % 95% CI value 95% CI LL UL LL UL RTS,S 0.1 PIII(D104) PIII(M13) PIII(M19) Control 1 PIII(D104) PIII(M13) PIII(M19) RTS,S 0.25 PIII(D104) PIII(M13) PIII(M19) Control 2 PIII(D104) PIII(M13) PIII(M19) RTS,S 0.5 PIII(D104) PIII(M13) PIII(M19) Control 3 PIII(D104) PIII(M13) PIII(M19) Pooled controls PIII(D104) PIII(M13) PIII(M19) N = number of subjects with available data n/% = number/percentage of subjects with anti-cs antibody concentrations 1 µg/ml 95% CI = 95% confidence interval; LL = Lower Limit; UL = Upper Limit PIII(D104) = Post-dose 3; Day 104 after the first vaccine dose PIII(M13) = Post-vaccination blood sample at Month 13 PIII(M19) = Post-vaccination blood sample at Month 19 Safety Results: Number (%) of subjects with unsolicited adverse events within the 30-day (Days 0-29) post-vaccination period (Total cohort) Most frequent adverse events On-Therapy (occurring within Days 0-29 following vaccination) RTS,S 0.1 Group Control 1 Group Subjects with any AE (s), n (%) 17 (85.0) 7 (70.0) 16 (80.0) 6 (30.0) 2 (20.0) 6 (30.0) Headache 4 (20.0) 1 (10.0) 5 (25.0) Abdominal pain 3 (15.0) 2 (20.0) 5 (25.0) Anorexia 2 (10.0) 1 (10.0) 1 (5.0) Diarrhea 1 (5.0) - - Diarrhea bloody 1 (5.0) - - Dyspepsia 1 (5.0) - - Tooth ache 1 (5.0) - - Tooth disorder 2 (10.0) - - Vomiting 1 (5.0) - 2 (10.0) Anemia (5.0) Abscess 1 (5.0) - - Infection 10 (50.0) 5 (50.0) 10 (50.0) Infection viral 1 (5.0) 1 (10.0) 1 (5.0) Otitis media 1 (5.0) - - Upper resp. tract infection 5 (25.0) 2 (20.0) 3 (15.0) RTS,S 0.25 Group

10 Coughing 1 (5.0) - 1 (5.0) Pneumonia (10.0 Dermatitis fungal 1 (5.0) - - Lymphadenopathy (5.0) Most frequent adverse events On-Therapy (occurring within Days 0-29 following vaccination) Control 2 Group RTS,S 0.5 Group Control 3 Group Subjects with any AE (s), n (%) 9 (90.0) 12 (60.0) 8 (80.0) 5 (50.0) 4 (20.0) 3 (30.0) Malaise - 1 (5.0) - Headache 2 (20.0) 1 (5.0) 2 (20.0) Abdominal pain 2 (20.0) - 1 (10.0) Anorexia - 1 (5.0) - Diarrhea 1 (10.0) - - Diarrhea bloody - 1 (5.0) - Tooth ache - 1 (5.0) - Earache 1 (10.0) - - Abscess 1 (10.0) 1 (5.0) - Infection 5 (50.0) 6 (30.0) 6 (60.0) Otitis media 1 (10.0) - 1 (10.0) Upper resp tract infection 2 (20.0) 4 (20.0) 3 (30.0) Pharyngitis - 1 (5.0) - Pneumonia (10.0) Dermatitis fungal 2 (20.0) 1 (5.0) - Nail disorder - 1 (5.0) - Skin ulceration 2 (20.0) - - -: Adverse event absent Safety results: Number (%) of subjects with serious adverse events throughout the primary study period (up to Month 9) (Total cohort) Serious adverse event, n (%) [n considered by the investigator to be related to study medication] All SAEs RTS,S 0.1 Group Control 1 Group RTS,S 0.25 Group Subjects with any SAE(s), n (%)[n assessed by the 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0] Fatal SAEs RTS,S 0.1 Group Control 1 Group RTS,S 0.25 Group Subjects with fatal SAE(s), n (%) [n assessed by the 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0] All SAEs Control 2 Group RTS,S 0.5 Group Control 3 Group Subjects with any SAE(s), n (%)[n assessed by the 0 (0.0) [0] 0 (0.0) [0] 1 (10.0) [0] Bronchopneumonia 0 (0.0) [0] 0 (0.0) [0] 1 (10.0) [0] Fatal SAEs Control 2 Group RTS,S 0.5 Group Control 3 Group Subjects with fatal SAE(s), n (%) [n assessed by the 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0] Safety results: Number (%) of subjects with serious adverse events between Month 4 and Month 21 post-dose 1 (Total cohort) Serious adverse event, n (%) [n considered by the investigator to be related to study medication] All SAEs RTS,S 0.1 Group Control 1 Group RTS,S 0.25 Group Subjects with any SAE(s), n (%)[n assessed by the 0 (0.0) [0] 0 (0.0) [0] 1 (5.0) [0] Head injury 0 (0.0) [0] 0 (0.0) [0] 1 (5.0) [0] Fatal SAEs RTS,S 0.1 Group Control 1 Group RTS,S 0.25 Group

11 Subjects with fatal SAE(s), n (%) [n assessed by the 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0] All SAEs Control 2 Group RTS,S 0.5 Group Control 3 Group Subjects with any SAE(s), n (%)[n assessed by the 1 (10.0) [0] 0 (0.0) [0] 0 (0.0) [0] Malaria NOS 1 (10.0) [0] 0 (0.0) [0] 0 (0.0) [0] Fatal SAEs Control 2 Group RTS,S 0.5 Group Control 3 Group Subjects with fatal SAE(s), n (%) [n assessed by the 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0] Conclusion: During the 4-day follow-up period after vaccination, the most frequently reported solicited local symptom was pain at the injection site, reported by at least 90.0% of subjects across groups and the most frequently reported solicited general symptom was headache, reported by 30.0% of subjects across groups. During the 30-day follow-up period after vaccination, at least one unsolicited AE was reported by 17 (85%) subjects in RTS,S 0.1 Group, 16 (80%) subjects in RTS,S 0.25 Group, 12 (60%) subjects in RTS,S 0.5 Group, 7 (70%) subjects in Control 1 Group, 9 (90%) subjects in Control 2 Group and 8 (80%) subjects in Control 3 Group. Up to Month 9, 1 SAE was reported in 1 subject from Control 3 Group; between Month 4 and Month 21, SAEs were reported in 1 subject from RTS,S 0.25 Group and in 1 subject from Control 2 Group. All SAEs reported during the primary and LT follow-up studies were assessed by the investigator as not related to vaccination; no fatal SAEs were reported. Publications: Bojang KA et al. (2005).Safety and immunogenicty of RTS,S/AS02A candidate malaria vaccine in Gambian children. Vaccine. 23(32): Date updated: 20March2013