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.: /002 Title: A phase I/II, open, controlled study in order to evaluate the reactogenicity and the immunogenicity of the GlaxoSmithKline Biologicals experimental influenza vaccine in an elderly population aged over 65 years (> 65 years-old) and previously vaccinated in 2003 with the experimental influenza vaccine in the Explo-Flu-001 clinical trial. For immunogenicity and safety evaluations, Fluarix vaccine (known as α-rix in Belgium) will be used as reference. Rationale: To evaluate the safety and the immunogenicity of a re-vaccination with an experimental influenza vaccine administered intramuscularly about 1 year after administration of the first dose of vaccine. Phase: I/II Study Period: 15 October 2004 to 25 November 2004 Study Design: Single centre, open, controlled study with two parallel groups. Two blood samples were taken; one just before vaccination and the other blood sample 21 days after vaccination. One group received an investigational vaccine formulation (experimental Influenza vaccine) that is not currently registered. Data from the group receiving currently registered vaccine (Control group) are presented. Data from the experimental vaccine will be reported after it is registered and marketed Centres: One centre in Belgium Indication: Immunization against influenza disease in elderly population aged over 65 years. Treatment: The study groups were as follows: - Experimental Group: received one dose of the experimental influenza vaccine at Day 0 - Control Group: received one dose of the commercial influenza split vaccine at Day 0 Both vaccines were administered intramuscularly in the deltoid region of the non-dominant arm. Objectives: To evaluate the safety of a revaccination with the experimental influenza vaccine during 21 days following the intramuscular administration of the vaccine. Commercially available influenza split vaccine was used as reference. Primary Outcome/Efficacy Variable: Percentage, intensity and relationship to vaccination of solicited local and general signs and symptoms during a 7 day (Days 0-6) follow-up period after vaccination. Percentage, intensity and relationship to vaccination of unsolicited local and general signs and symptoms during a 21 day (Days 0-20) follow-up period after vaccination. Occurrence of serious adverse events during the entire study. Secondary Outcome/Efficacy Variable(s): For the humoral immune response - Observed variables: At days 0 and 21: serum haemagglutination-inhibition (HI) antibody titres, tested separately against each of the three influenza virus strains represented in the vaccine (anti-h1n1, anti-h3n2, and anti-b-antibodies) At days 0 and 21: neutralising antibody titres, tested separately against each of the three influenza virus strains represented in the vaccine. - Derived variables [with 95% confidence interval ()]: Geometric mean titres (GMTs) of serum HI and neutralising antibodies pre- and post-vaccination Seroconversion rates of serum HI and neutralising antibodies at day 21 defined as the percentage of vaccinees that have at least a 4-fold increase in serum antibody titres on day 21 compared to day 0, for each vaccine strain Conversion factors at day 21 defined as the fold increase in serum HI GMTs on day 21 compared to day 0, for each vaccine strain Seroprotection rates defined as the percentage of vaccinees with a serum HI titre 1:40 after vaccination, for each vaccine strain Seropositivity rates defined as the percentage of vaccinees with a serum HI titre 1:10 after vaccination, for each vaccine strain For the cell mediated immune (CMI) response At days 0 and 21: frequency of influenza-specific CD4/CD8 cells per million (10 6 ) Cells producing at least two different cytokines [Cluster differentiation-40l (CD40L), Interleukin-2 (IL-2), Interferon-γ (IFNγ), Tumour Necrosis Factor alpha (TNFα)] Cells producing at least CD40L and another signal molecule (IL-2, IFNγ, TNFα) Cells producing at least IL-2 and another signal molecule (CD40L, IFN-γ, TNF-α) Cells producing at least IFN-γ and another signal molecule (CD40L, IL-2, TNF-α) 1

2 Cells producing at least TFN-α and another signal molecule (IL-2, IFN-γ, CD40L) Difference between post-and pre-vaccination frequencies of influenza-specific CD4/CD8 cells Difference between post- and pre-vaccination frequencies of influenza-specific antibody forming cells Influenza specific memory B-cells measured by B-cell Elispot in term of frequency of influenza-specific antibody forming cells per million of antibody forming cells Statistical Methods: The analyses were performed on the Total vaccinated cohort. - The Total Vaccinated cohort included all vaccinated subjects for whom data were available. Analysis of Immunogenicity: The analysis of immunogenicity was performed on the Total vaccinated cohort. Humoral immune response The results of humoral immune response were evaluated by comparison with the European Union (EU) requirements for Influenza vaccines in subjects aged over 60 years [Committee for Proprietary Medicinal Products (CPMP), 12 March 1997]. GMTs of HI antibody titres and GMTs of anti-neutralising titres for the three influenza virus strains represented in the vaccine (H1N1, H3N2 and B) were tabulated with at pre-and post-vaccination. Seroprotection rates of HI antibody titres for the three influenza virus strains represented in the vaccine (H1N1, H3N2 and B) were tabulated with at pre-and post-vaccination. Seroconversion rates of HI antibody titres and anti-neutralising titres for the three influenza virus strains represented in the vaccine (H1N1, H3N2 and B) were tabulated with. Conversion factor (Geometric Mean Ratio) of HI antibody titres for the three influenza virus strains represented in the vaccine (H1N1, H3N2 and B) was tabulated with. Cell-mediated immune response The frequency of influenza-specific CD4/CD8 T-lymphocytes and influenza specific memory B-cells (measured by B-cell Elispot) per million of CD4/CD8 T-lymphocytes was summarised using descriptive statistics at days 0 and 21 for each influenza antigen. The frequency of influenza-specific antibody forming cells per million of antibody forming cells was summarised using descriptive statistics at days 0 and 21 for each influenza antigen. Descriptive statistics of the individual difference between day 21 and day 0 (Post-Pre vaccination) responses were calculated for each antigen. Analysis of Safety: The analysis of safety was performed on the Total vaccinated cohort. The percentage of subjects reporting each individual solicited local and general adverse event during the 7-day (Days 0-6)) follow-up period after vaccination was tabulated with exact. The frequency of unsolicited symptoms and serious adverse events reported up to 21 days (day0-day20) after vaccination were tabulated according to the Medical Dictionary for Regulatory Activities (MedDRA) preferred term. Study Population: Male or female subjects aged over 65 years at the time of the revaccination, previously vaccinated in 2003 with the influenza vaccine and who were free of an acute aggravation of the health status. Subjects with a history of confirmed influenza infection since a year from the date of previous vaccination or acute clinically significant pulmonary, cardiovascular, hepatic, or renal functional abnormality were excluded. Number of Subjects: Planned, N 20 Randomised, N (Total vaccinated Cohort) 18 Completed, n (%) 18 (100) Total Number Subjects Withdrawn, n (%) 0 (0.0) Withdrawn due to Adverse Events, n (%) 0 (0.0) Withdrawn due to Lack of Efficacy, n (%) Not applicable Withdrawn for other reasons, n (%) 0 (0.0) Demographics N (Total Vaccinated Cohort) 18 Females: Males 11:7 Mean Age, years (SD) 70.6 (3.87) Caucasian, n (%) 18 (100) Primary Efficacy Results: Percentage of subjects reporting solicited local symptoms during the 7-day (Days 0-6) post-vaccination period in the control group (Total vaccinated Cohort) Symptom Intensity N n % 95 % CI 2

3 Haematoma Any mm Pain Any Redness Any mm Swelling Any mm N= number of subjects with at least one symptom sheet completed n/%= number/percentage of subjects with at least once the symptom Any = incidence of a particular symptom regardless of grade Grade 3 Pain = symptom that prevented normal everyday activities 95%CI = Exact 95% confidence interval; = lower limit, = upper limit Primary Efficacy Results: Percentage of subjects reporting solicited general symptoms during the 7-day (Days 0-6) post-vaccination period in the control group (Total vaccinated cohort) Symptom Intensity/ Relationship N n % 95 % CI Fatigue Any Related Fever 37.5 C (Axillary) >39.0 C Related Headache Any Related Joint pain in the arm of the injection Any Related Joint pain at other location Any Related Muscle aches Any Related Shivering Any Related N= number of subjects with at least one symptom sheet completed n/%= number/percentage of subjects reporting at least once the symptom Any = incidence of a particular symptom regardless of grade or relationship to vaccinations Grade 3 for all symptoms = adverse event which prevented normal everyday activities Related = the investigator determined that there was a reasonable possibility that the study vaccine contributed to the solicited general event 95%CI = Exact 95% confidence interval; = lower limit, = upper limit Seropositivity rates (S+), and GMTs of anti-hi titers for each vaccine strain at pre- and post-vaccination in the control group (Total vaccinated cohort) Strain Timing N S+ ( 10 1/DIL) GMT n % Value A/New Caledonia PRE (H1N1) PI(D21) A/Wyoming PRE (H3N2) PI(D21) B/Jiangsu PRE

4 (B) PI(D21) N = number of subjects with available results n/% = number/percentage of subjects with titre within the specified range PRE = Pre-vaccination, PI(D21) = 21 days post-vaccination = 95% confidence interval, = lower limit, = upper limit Seroprotection rates of anti-hi titres for each vaccine strain at pre and post-vaccination in the control group (Total vaccinated cohort) Strain Timing N n % A/New Caledonia PRE (H1N1) PI(D21) A/Wyoming PRE (H3N2) PI(D21) B/Jiangsu PRE (B) PI(D21) N = number of subjects with available results n/% = number/percentage of subjects with titre within the specified range PRE = Pre-vaccination, PI(D21) = 21 days post-vaccination = 95% confidence interval, = lower limit, = upper limit European Union requirement for the seroprotection rate (post-vaccination) for age group >60 years: >60% Seroconversion rates of anti-hi titres for each vaccine strain at day 21 in the control group (Total vaccinated cohort) Strain N Responders (fold-increase 4) n % A/New Caledonia (H1N1) A/Wyoming (H3N2) B/Jiangsu (B) N = number of subjects with both pre and post vaccination result available n/% = number/proportion of responders = exact 95% confidence interval, = lower limit, = upper limit European Union requirement for the seroprotection rate (post-vaccination) for age group > 60 years: >30% Conversion factor of anti-hi titres for each vaccine strain at day 21 in the control group (Total vaccinated cohort) Strain N GMR 95 % CI A/New-Caledonia (H1N1) A/Wyoming (H3N2) B/Jiangsu (B) N = total number of subjects GMR = Geometric Mean Ratio (antilog of the mean log day 21/day 0 titres ratios) = 95% confidence interval, = lower limit, = upper limit European Union requirement for the conversion factor (post-vaccination) for age group >60 years: >2.0 GMTs for anti-neutralising titres for each vaccine strain at pre and post-vaccination in the control group (Total vaccinated cohort) Strain Timing N GMT value A/New Caledonia (H1N1) PRE PI(D21) A/Wyoming (H3N2) PRE PI(D21) B/Jiangsu (B) PRE PI(D21) N = number of subjects with available results = 95% confidence interval; = Lower Limit, = Upper Limit, PRE = Pre-vaccination, PI(D21) = 21 days post-vaccination Seroconversion rates of anti-neutralising titres for each vaccine strain at day 21 in the control group (Total vaccinated cohort) 4

5 Strain N Responders (fold-increase 4) n % A/New Caledonia (H1N1) A/Wyoming (H3N2) B/Jiangsu (B) N = number of subjects with both pre and post vaccination result available n/% = number/proportion of responders = exact 95% confidence interval; = lower limit, = upper limit European Union requirement for the seroprotection rate (post-vaccination): >30% Descriptive Statistics at pre- and post-vaccination for the antigen-specific CD4 T-lymphocytes responses in the control group (Total vaccinated cohort) Strain Cytokine Timing N Mean SD Pool Flu A DOUBLE PRE PI(D21) CD40L PRE PI(D21) IFNγ PRE PI(D21) IL2 PRE PI(D21) TNFα PRE PI(D21) A/New Caledonia A DOUBLE PRE (H1N1) PI(D21) CD40L PRE PI(D21) IFNγ PRE PI(D21) IL2 PRE PI(D21) TNFα PRE PI(D21) A/Wyoming A DOUBLE PRE (H3N2) PI(D21) CD40L PRE PI(D21) IFNγ PRE PI(D21) IL2 PRE PI(D21) TNFα PRE PI(D21) B/Jiangsu A DOUBLE PRE (B) PI(D21) CD40L PRE PI(D21) IFNγ PRE PI(D21) IL2 PRE PI(D21) TNFα PRE PI(D21) PRE = Pre-vaccination PI(D21) = 21 days post-vaccination 5

6 All double: cells producing at least two different cytokines (CD40L, IFNγ, IL-2, TFNα) CD40L: cells producing at least CD40L and another cytokine (IFNγ, IL-2, TFNα) IFNγ: cells producing at least IFNγ and another cytokine (CD40L, IL-2, TFNα) IL-2: cells producing at least IL-2 and another cytokine (CD40L, IFNγ, TFNα) TFNα: cells producing at least TFNα and another cytokine (CD40L, IL-2, IFNγ) Descriptive Statistics of the difference between post- and pre-vaccination (Day 21 - Day 0) for the antigen-specific CD4 T-lymphocyte responses in the control group (Total vaccinated cohort) Strain Cytokine N Mean SD Pool Flu A DOUBLE CD40L IFNγ IL TNFα A/New Caledonia (H1N1) A DOUBLE CD40L IFNγ IL TNFα A/Wyoming (H3N2) A DOUBLE CD40L IFNγ IL TNFα B/Jiangsu (B) A DOUBLE CD40L IFNγ IL TNFα All double: cells producing at least two different cytokines (CD40L, IFNγ, IL-2, TFNα) CD40L: cells producing at least CD40L and another cytokine (IFNγ, IL-2, TFNα) IFNγ: cells producing at least IFNγ and another cytokine (CD40L, IL-2, TFNα) IL-2: cells producing at least IL-2 and another cytokine (CD40L, IFNγ, TFNα) TFNα: cells producing at least TFNα and another cytokine (CD40L, IL-2, IFNγ) Descriptive Statistics at pre- and post-vaccination for the antigen-specific CD8 T-lymphocytes responses in the control group (Total vaccinated cohort) Strain Cytokine Timing N Mean SD Pool Flu A DOUBLE PRE PI(D21) CD40L PRE PI(D21) IFNγ PRE PI(D21) IL2 PRE PI(D21) TNFα PRE PI(D21) A/New A DOUBLE PRE Caledonia (H1N1) PI(D21) CD40L PRE PI(D21) IFNγ PRE PI(D21) IL2 PRE

7 PI(D21) TNFα PRE PI(D21) A/Wyoming A DOUBLE PRE (H3N2) PI(D21) CD40L PRE PI(D21) IL2 PRE PI(D21) IFNγ PRE PI(D21) TNFα PRE PI(D21) B/Jiangsu A DOUBLE PRE (B) PI(D21) CD40L PRE PI(D21) IFNγ PRE PI(D21) IL2 PRE PI(D21) TNFα PRE PI(D21) PRE = Pre-vaccination PI(D21) = 21 days post-vaccination All double: cells producing at least two different cytokines (CD40L, IFNγ, IL-2, TFNα) CD40L: cells producing at least CD40L and another cytokine (IFNγ, IL-2, TFNα) IFNγ: cells producing at least IFNγ and another cytokine (CD40L, IL-2, TFNα) IL-2: cells producing at least IL-2 and another cytokine (CD40L, IFNγ, TFNα) TFNα: cells producing at least TFNα and another cytokine (CD40L, IL-2, IFNγ) Descriptive Statistics of the difference between post- and pre-vaccination (Day 21-Day 0) for the antigen-specific CD8 T-lymphocyte responses in the control group (Total vaccinated cohort) Strain Cytokine N Mean SD Pool Flu A DOUBLE CD40L IFNγ IL TNFα A/New Caledonia (H1N1) A DOUBLE CD40L IFNγ IL TNFα A/Wyoming (H3N2) A DOUBLE CD40L IL IFNγ TNFα B/Jiangsu (B) A DOUBLE CD40L IFNγ IL TNFα

8 All double: cells producing at least two different cytokines (CD40L, IFNγ, IL-2, TFNα) CD40L: cells producing at least CD40L and another cytokine (IFNγ, IL-2, TFNα) IFNγ: cells producing at least IFNγ and another cytokine (CD40L, IL-2, TFNα) IL-2: cells producing at least IL-2 and another cytokine (CD40L, IFNγ, TFNα) TFNα: cells producing at least TFNα and another cytokine (CD40L, IL-2, IFNγ) B-cell memory ELISPOT: Descriptive Statistics at days 0 and 21 for frequency of specific-plasma within a million of IgG producing plasma cells in the control group (Total vaccinated cohort) Strain Timepoint N Mean SD A/New Caledonia (H1N1) PRE PI(D21) A/Wyoming (H3N2) PRE PI(D21) B/Jiangsu (B) PRE PI(D21) PRE = Pre-vaccination, PI(D21) = 21 days post-vaccination B-cell memory ELISPOT: Descriptive Statistics of the difference between day 21 and day 0 for the frequency of specific-plasma within a million of IgG producing plasma cells in the control group (Total Vaccinated Cohort) Strain N Mean SD A/New Caledonia (H1N1) A/Wyoming (H3N2) B/Jiangsu (B) Safety results: Number (%) of subjects with unsolicited adverse events (Total vaccinated cohort) Serious adverse events, n (%) [n considered by the investigator to be related to the medication] Most frequent adverse events - On-Therapy (occurring within day 0-20 following vaccination) (N = 18) Subjects with any AE(s), n (%) 4 (22.2) Subjects with adverse events classified as severe, n (%) 0 (0.0) Subjects with adverse events classified as related, n (%) 0 (0.0) Upper respiratory tract infection 2 (11.1) Hyperhidrosis 1 (5.6) Nasopharyngitis 1 (5.6) Phlebitis 1 (5.6) Safety results: Number (%) of subjects with serious adverse events (SAEs) (Total vaccinated cohort) All SAEs (N = 18) Subjects with any SAE(s), n (%) [n related] 0 (0.0) [0] Fatal SAEs (N = 18) Subjects with fatal SAE(s), n (%) [n related] 0 (0.0) [0] 8

9 Conclusion: The commercial influenza split vaccine fulfilled the requirement of the EU authorities for annual registration of influenza inactivated vaccines, where at least one of the assessments should be met (seroconversion rate, seroconversion factor, seroprotection rate). The seroprotection rate and seroconversion factor were superior to the regulatory threshold for all strains. The seroconversion rate for the H1N1 antigens (A/New Caledonia) after vaccination for the commercial influenza split vaccine was lower than the regulatory threshold of 30% for subjects aged over 60 years due to the high pre-vaccination antibody titres. Pain at the injection site was the most frequently reported solicited local symptom. No severe solicited general symptoms were reported. Four subjects reported five unsolicited symptoms. No serious adverse events (fatal or non-fatal) were reported. Publications: No publication Date Updated: 27-Jun