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.: /024 (HSV-024) Title: A double blind, randomized trial comparing the immunogenicity of 3 commercial scale consistency lots of gd-alum- MPL vaccine containing CHO K1 gd in healthy HSV seronegative adult subjects. gd-alum/mpl (HSV): GlaxoSmithKline (GSK) Biologicals candidate herpes simplex vaccine. MPL: 3-deacylated form of Monophosphoryl Lipid A (3D MPL) Rationale: The aim of this study was to compare the immunogenicity of 3 different commercial scale production lots of the HSV vaccine. The safety of the vaccine was also assessed. Phase: III Study Period: 15 October 1996 to 07 June 1999 Study Design: Double-blind, randomized (1:1:1) multicentre study with 3 parallel groups. Centers: 2 centers in United States Indication: Prevention of genital herpes disease Treatment: There were 3 groups in this study: : subjects received 3 doses of HSV vaccine lot A : subjects received 3 doses of HSV vaccine lot B : subjects received 3 doses of HSV vaccine lot C The vaccine was administered intramuscularly in the deltoid region of the non-dominant arm according to a 0, 1, 6 months schedule. Objectives: To compare, one month after the third dose of vaccine, the anti-glycoprotein D from HSV-2 (anti-gd2) antibody responses in 3 groups of healthy HSV seronegative subjects receiving the HSV vaccine from 3 different commercial scale production lots. Primary Outcome/Efficacy Variable: To compare geometric mean titers (GMTs) of anti-gd2 antibodies measured one month after the third dose of vaccine in three groups of healthy HSV seronegative subjects receiving the HSV vaccine from 3 different commercial scale production lots. Secondary Outcome/Efficacy Variable(s): To evaluate GMTs of anti-hsv-2 neutralizing antibody measured one month after the third dose of vaccine in three groups of healthy HSV seronegative subjects receiving the HSV vaccine from 3 different commercial scale production lots. To evaluate the cell mediated immune (CMI) responses (lymphoproliferation, secretion of interleukin (IL) 5 and of gamma interferon ( -IFN)) measured one month after the third dose of vaccine in three groups of healthy HSV seronegative subjects receiving the HSV vaccine from 3 different commercial scale production lots. To evaluate, in three groups of healthy HSV seronegative subjects receiving the HSV vaccine from 3 different commercial scale production lots, the incidence and intensity of solicited local and general signs and symptoms during the day of vaccination and the 3 days after each dose of each vaccine. To evaluate the overall safety of the 3 different commercial scale production lots of HSV vaccine. All unsolicited symptoms occurring within the 30-day period following each dose of vaccine* and all serious unsolicited symptoms occurring throughout the entire study period have been evaluated with respect to the type, frequency and severity of the experiences. To evaluate the persistence of immune responses, GMTs of anti-gd2 and neutralizing antibody, and each of the cell mediated immune responses assayed (lymphoproliferation, IL-5 and -IFN; in a subset of study subjects) have been evaluated using samples collected from subjects at months 12 and 24 of the study. *Unsolicited symptoms were evaluated during a 31-day period following each dose of vaccine. Statistical Methods: Analyses were performed on the Total Vaccinated cohort, the According to Protocol (ATP) cohort for safety and the ATP cohort for immunogenicity. The Total Vaccinated cohort included all subjects who received at least one dose of the vaccine. The ATP cohort for safety included all subjects who received the first dose of vaccine, with sufficient data (at least one solicited or unsolicited symptom sheet available), who had not received a vaccine not specified or forbidden

2 by the protocol within one week before or after a dose of study vaccine, without randomization failure or code broken, for whom injection site or route of vaccine administration was known and correct. The ATP cohort for immunogenicity included all evaluable subjects (i.e., those meeting all eligibility criteria, complying with the procedures defined in the protocol, and fulfilling requirements for analysis) for whom pertinent data were available. This included subjects for whom at least one anti-gd2 result was available for at least one post dose 3 blood-sampling time point. Analysis of Immunogenicity: The analysis of immunogenicity was performed on the ATP cohort for immunogenicity. Inferential analysis: For each pair of 2 groups (lots), the 86% confidence interval (CI) for the ratio of GMTs was computed using ANOVA model on the logarithm of titers and the p-values measured simultaneously the distance between the lower limit (LL) of the 86% CI and the LL of the equivalence region and the distance between the upper limit (UL) of the 86% CI and the UL of the equivalence region. Consistency was concluded only if the three 86% Cls were included in the equivalence region, the p- values had to be inferior to 0.07 and the highest p-value was the overall p-value, summarizing all the pair wise comparisons. Descriptive analysis: GMTs with their 95% CI for anti-gd2 measured by ELISA assay and anti-hsv-2 measured by neutralizing assay were calculated one month after the third dose of vaccine in all subjects of the 3 groups. For CMI evaluation, descriptive statistics were calculated for IL-5, -IFN and lymphoproliferation measured one month after the third dose of vaccine on a subset of the population in each group. The persistence of immune responses, GMTs of anti-gd2 and neutralizing antibodies, and each of the CMI responses (lymphoproliferation, IL-5 and -IFN; in a subset of study subjects) were evaluated using samples collected from subjects at months 12 and 24 of the study. Analysis of Safety The analysis of safety was performed on the ATP cohort for safety. The incidence of solicited local and general symptoms during the day of vaccination and the 3 days after each dose of vaccine was tabulated with exact 95% CI for each group. The same calculations were performed for grade 3 symptoms (only across doses), and for general symptoms assessed by the investigators as related to vaccination. All solicited local symptoms were assessed as causally related to the vaccination. The percentages of subjects with at least one report of an unsolicited adverse event (AE) classified by World Health Organization s (WHO) preferred term occurring within the 31-day (Day 0-30) period following each vaccine dose were tabulated for each treatment group. The same tabulation was performed for grade 3 unsolicited AEs. SAEs were collected and summarized by WHO preferred terms during the entire study period, i.e. from Month 0 to Month 24. Study Population: Healthy male and female volunteers aged 18 45, who were seronegative for HSV-1 and HSV-2 (by gd2 ELISA), who had not been previously vaccinated against herpes simplex virus and had no current signs or symptoms of genital or orolabial herpes disease. Female volunteers of childbearing potential had to have a negative pregnancy test at enrollment and had to use an accepted method of birth control. Written informed consent was obtained from the subject prior to study entry. Number of Subjects Planned, N Randomized, N (Total Vaccinated cohort) Completed, n (%) 61 (91.0) 63 (88.7) 57 (87.7) Total Number Subjects Withdrawn, n (%) 6 (9.0) 8 (11.3) 8 (12.3) Withdrawn due to Adverse Events n (%) 0 (0.0) 0 (0.0) 1 (1.5) Withdrawn due to Lack of Efficacy n (%) Not applicable Not applicable Not applicable Withdrawn for other reasons n (%) 6 (9.0) 8 (11.3) 7 (10.8) Demographics N (Total Vaccinated cohort) Females: Males 33:34 36:35 34:31 Mean Age, years (SD) 26.5 (7.78) 26.8 (7.19) 26.5 (7.99) White/Caucasian n (%) 61 (91.0) 69 (97.2) 57 (87.7) Primary Efficacy Results: Ratio of geometric mean titers (GMTs) for anti-gd2 (measured by ELISA) antibody one month

3 after the third vaccination (ATP cohort for immunogenicity). Ratios of GMT P value* Value 86% CI LL UL / / / Overall % CI = 86% confidence interval; LL= Lower Limit; UL: Upper Limit *Equivalence criterion: The p-values for the comparisons for each pair of two groups and the highest of these three p-values summarized all the pair wise comparisons inferior to 0.07 Primary Efficacy Results: Seropositivity rates and GMTs of anti-gd2 (measured by ELISA) antibody (ATP cohort for immunogenicity) Seropositivity rate GMT* Group Timing N n % 95 % CI Value 95 % CI HSV A Pre PII(M2) PII(M6) PIII(M7)* PIII(M12) PIII(M24) HSV B Pre PII(M2) PII(M6) PIII(M7)* PIII(M12) PIII(M24) HSV C Pre PII(M2) PII(M6) PIII(M7)* PIII(M12) PIII(M24) Subjects with titers 40 EU/mL were considered as seropositive N = number of subjects with available result n / % = number / percentage of seropositive subjects 95% CI = 95% confidence interval LL: Lower Limit; UL: Upper Limit PIII(M12) = post dose 3 blood sampling at month 12 *Primary Outcome results Secondary Outcome Variable(s): Seropositivity rates and GMTs of anti-hsv2 (measured by neutralization) antibody.(atp cohort for immunogenicity) Seropositivity rate GMT Group Timing 95 % CI N n % 95 % CI Value LL UL HSV A Pre PII(M2) PII(M6) PIII(M7) PIII(M12)

4 PIII(M24) HSV B Pre PII(M2) PII(M6) PIII(M7) PIII(M12) PIII(M24) HSV C Pre PII(M2) PII(M6) PIII(M7) PIII(M12) PIII(M24) N = number of subjects with the available result n / % = number / percentage of seropositive subjects, i.e. number of subjects with titers equal to or above 4 95% CI = 95% confidence interval LL: Lower Limit; UL: Upper Limit PIII(M12) = post dose 3 blood sampling at month 12 Secondary Outcome Variable(s): Summary of cell mediated immune response: lymphoproliferation stimulation dose 10 µg/ml (ATP cohort for immunogenicity - CMI-subset) Method Group Timing N Mean STD Median Method 1 HSV A Pre PII(M2) PII(M6) PIII(M7) PIII(M12) HSV B Pre PII(M2) PII(M6) PIII(M7) PIII(M12) HSV C Pre PII(M2) PII(M6) PIII(M7) PIII(M12) Method 2 HSV A PIII(M24) HSV B PIII(M24) HSV C PIII(M24) A different method was used for the analysis of CMIs: Method 1 used at Month 0, 2, 6, 7 and 12= ratio of the arithmetic mean of the 3 counts per minute (cpm) values observed at the considered dose by the arithmetic mean of the 3 cpm values observed at background Method 2 used at Month 24= ratio of the geometric mean of the 3 cpm values observed at the considered dose by the geometric mean of the 3 cpm values observed at background. N = Number of subjects tested STD = Standard deviation

5 PIII(M12) = post dose 3 blood sampling at month 12 Secondary Outcome Variable(s): Summary of cell mediated immune response: secretion of IL-5 stimulation dose 10 µg/ml (ATP cohort for immunogenicity - CMI-subset) Method Group Timing N Mean STD Median Method 1 HSV A Pre PII(M2) PII(M6) PIII(M7) PIII(M12) HSV B Pre PII(M2) PII(M6) PIII(M7) PIII(M12) HSV C Pre PII(M2) PII(M6) PIII(M7) PIII(M12) Method 2 HSV A PIII(M24) HSV B PIII(M24) HSV C PIII(M24) A different method was used for the analysis of CMIs: Method 1 used at Month 0, 2, 6, 7 and 12= ratio of the arithmetic mean of the 3 cpm values observed at the considered dose by the arithmetic mean of the 3 cpm values observed at background Method 2 used at Month 24= ratio of the geometric mean of the 3 cpm values observed at the considered dose by the geometric mean of the 3 cpm values observed at background. N = Number of subjects tested STD = Standard deviation PIII(M12) = post dose 3 blood sampling at month 12 Secondary Outcome Variable(s): Summary of cell mediated immune response: secretion of IFN stimulation dose 10 µg/ml (ATP cohort for immunogenicity - CMI-subset) Method Group Timing N Mean STD Median Method 1 HSV A Pre PII(M2) PII(M6) PIII(M7) PIII(m12) HSV B Pre PII(m2) PII(m6) PIII(m7) PIII(m12) HSV C Pre PII(m2) PII(m6) PIII(m7) PIII(M12) Method 2 HSV A PIII(M24)

6 HSV B PIII(M24) HSV C PIII(M24) A different method was used for the analysis of CMIs: Method 1 used at Month 0, 2, 6, 7 and 12= ratio of the arithmetic mean of the 3 cpm values observed at the considered dose by the arithmetic mean of the 3 cpm values observed at background Method 2 used at Month 24= ratio of the geometric mean of the 3 cpm values observed at the considered dose by the geometric mean of the 3 cpm values observed at background. N = Number of subjects tested STD = Standard deviation PIII(M12) = post dose 3 blood sampling at month 12 Secondary Outcome Variable(s): Incidences of any solicited local symptoms during the 4-day follow-up period following the administration of each vaccine dose and across doses. (ATP cohort for safety) (N=64) (N=70) (N=63) 95%CI 95%CI 95%CI Symptom Intensity n % LL UL n % LL UL n % LL UL Dose 1 Soreness Any Grade Muscle Any stiffness Grade Redness Any Grade Swelling Any Grade (N=61) (N=66) (N=63) Dose 2 Soreness Any Grade Muscle Any stiffness Grade Redness Any Grade Swelling Any Grade (N=62) (N=58) (N=61) Dose 3 Soreness Any Grade Muscle Any stiffness Grade Redness Any Grade Swelling Any Grade (N=64) Across Doses (N=70) (N=64)

7 Soreness Any Grade Muscle Any stiffness Grade Redness Any Grade Swelling Any Grade N= number of subjects with the documented dose n/%= number/percentage of subjects reporting at least once the symptom 95%CI= Exact 95% confidence interval; LL = lower limit, UL = upper limit Any= occurrence of any local symptom, regardless of intensity grade Grade 3 soreness and muscle stiffness = symptoms that prevented normal everyday activities Grade 3 redness and swelling 30 mm and persisting more than 24 hours Secondary Outcome Variable(s): Incidences of any solicited general symptoms during the 4-day follow-up period following the administration of each vaccine dose and across doses (ATP cohort for safety) 95% CI 95% CI 95% CI Symptom Intensity/ Relationship n % LL UL n % LL UL n % LL UL Dose 1 Fever (oral) > 37.5 C > 39 C Related Headache Any Related Malaise Any Related Fatigue Any Related (N = 61) (N = 66) (N = 63) Dose 2 Fever (oral) > 37.5 C > 39 C Related Headache Any Related Malaise Any Related Fatigue Any Related (N = 62) (N = 59) (N = 61) Dose 3 Fever (oral) > 37.5 C > 39 C Related

8 Headache Any Related Malaise Any Related Fatigue Any Related Across Doses Fever (oral) > 37.5 C > 39 C Related Headache Any Grade Related Malaise Any Grade Related Fatigue Any Grade Related : Grade 3 results are not available for individual doses. N= number of subjects with the documented dose n/%= number/percentage of subjects reporting at least once the symptom 95% CI= Exact 95% confidence interval; LL = lower limit, UL = upper limit Any = occurrence of any solicited general symptom, regardless of intensity or relationship to vaccination Grade 3 symptom = general symptom that prevented normal everyday activities Related = general symptom assessed by the investigator as probably associated with, or suspected to be causally related to the study vaccination Safety results: Number (%) of subjects with unsolicited symptoms reported within the 31-day post-vaccination period (ATP cohort for safety) Most frequent adverse events - On-Therapy (occurring within Day 0-30 following vaccination) Subjects with any AE(s), n (%) 10 (15.6) 19 (27.1) 25 (38.5) Subjects with grade 3 AE(s), n (%) 1 (1.6) 0 (0.0) 1 (1.5) Erythema nodosum (1.5) Pruritus (1.5) Rash maculo-papular (1.5) Arthralgia - 1 (1.4) - Back pain - 2 (2.9) 1 (1.5) Myalgia - 2 (2.9) 1 (1.5) Tendinitis - 1 (1.4) 1 (1.5) Dizziness - 1 (1.4) - Headache 1 (1.6) 2 (2.9) 1 (1.5) Hypertonia - 1 (1.4) - Migraine - 1 (1.4) - Blepharitis (1.5) Depression - 1 (1.4) - Nervousness - 1 (1.4) - Diarrhea 1 (1.6) - 1 (1.5) Dyspepsia - 1 (1.4) -

9 Flatulence 1 (1.6) - - Gastric ulcer (1.5) Vomiting (1.5) Bronchitis 1 (1.6) - 3 (4.6) Coughing - 1 (1.4) - Laryngitis 1 (1.6) - - Pharyngitis (1.5) Rhinitis 2 (3.1) - 4 (6.2) Sinusitis 1 (1.6) 3 (4.3) - Lymphadenopathy - 1 (1.4) - Urinary tract infection 1 (1.6) 1 (1.4) 1 (1.5) Dysmenorrhea 1 (1.6) 1 (1.4) 2 (3.1) Chest pain (1.5) Influenza-like symptoms (1.5) Injury 1 (1.6) 1 (1.4) - Malaise - 1 (1.4) - Pain - 1 (1.4) - Injection site reaction - 3 (4.3) 4 (6.2) Infection bacterial 1 (1.6) - - Infection viral 1 (1.6) 1 (1.4) 1 (1.5) Upper respiratory tract infection 1 (1.6) 3 (4.3) 7 (10.8) -: AE absent Grade 3 = AE which prevented normal, everyday activities Safety Results: Number (%) of subjects with serious adverse events during the entire study period (ATP cohort for safety) Serious adverse event, n (%) [n considered by the investigator to be related to study medication] All SAEs Subjects with any SAE(s), n (%) [n assessed by the investigator 0 (0.0) [0] 0 (0.0) [0] 2 (3.1) [0] as related] Abortion 0 (0.0) [0] 0 (0.0) [0] 1 (1.5) [0] Breast neoplasm malignant female 0 (0.0) [0] 0 (0.0) [0] 1 (1.5) [0] Fatal SAEs Subjects with fatal SAE(s), n (%) [n assessed by the investigator as related] 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0] Conclusion: One month after the third vaccination (Month 7) the anti-gd2 GMTs were , and for the HSV A, HSV B and HSV C groups, respectively. Within 31 days post-vaccination, 10 (15.6%), 19 (27.1%) and 25 (38.5%) subjects in the HSV A, HSV B and HSV C groups, respectively, reported at least one unsolicited AE. From Month 0 to Month 24, SAEs were reported for 2 subjects (3.1%) in the. None of these SAEs were assessed by the investigators as related to the vaccination. No fatal SAEs were reported during the study. Publications: None Date updated: 27-Sept-2011