GSK Medicine: GlaxoSmithKline Biologicals (GSK) AS03-adjuvanted monovalent pandemic influenza H5N1 or H1N1 vaccines manufactured in Quebec or Dresden

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1 GSK Medicine: GlaxoSmithKline Biologicals (GSK) AS03adjuvanted monovalent pandemic influenza H5N1 or H1N1 vaccines manufactured in Quebec or Dresden Study No.: Flu QPAN (H5N1+ H1N1) Integrated summary of Safety (ISS) Title: Integrated summary of the safety of AS03adjuvanted monovalent H5N1 and H1N1 vaccines in adults 18 years of age and older. Rationale: The aim of the current integrated summary of safety (ISS) was to pool the safety data of 28 clinical trials of GSK s AS03adjuvanted Quebecmanufactured (QPan) and Dresdenmanufactured (DPan) pandemic H5N1 and H1N1 vaccines* administered in adults subjects. This provided an opportunity to pool the safety experience of subjects from several studies, in an effort to identify less common and medically more serious events, through the evaluation of all available data from adult recipients of GSK s AS03adjuvanted DPAN and QPAN H5N1 and H1N1 vaccines. Special attention was given in this ISS to medicallyattended adverse events (MAEs), serious adverse events (SAEs), potential immunemediated diseases (pimds) and adverse events of special interest (). *The vaccines administered as part of the analyses pooled in this ISS were: Pandemrix : GSK s H1N1 pandemic influenza vaccine, adjuvanted, manufactured in Dresden, Germany Arepanrix : GSK s H1N1 pandemic influenza vaccine, adjuvanted, manufactured in Quebec, Canada Prepanrix : GSK s H5N1 prepandemic influenza vaccine, adjuvanted, manufactured in Dresden, Germany Pumarix : GSK s H5N1 prepandemic influenza vaccine, adjuvanted, manufactured in Quebec, Canada Objectives: To develop an estimate of the incidence of medicallyattended adverse events (MAEs) and serious adverse events (SAEs) after the primary vaccination series based on the maximum sample size attainable in subjects with comparable data. To increase the likelihood of detecting rare adverse events, and more specifically potential immunemediated diseases (pimds), in order to generate hypotheses as to whether these could represent adjuvanted (pre) pandemic influenza vaccineattributable safety findings that merit further examination. Indication: Influenza disease caused by an influenza virus with pandemic potential containing H5N1 or H1N1 strains in adults 18 years of age or older. Study Investigators/Centers: GSK conducted study Research Methods: Data Source: The ISS compiled safety data from adult clinical trials that evaluated primary vaccination with inactivated H5N1 or H1N1 antigens combined with the adjuvant system AS03 and manufactured in GSK s facilities in Quebec, Canada, or Dresden, Germany. All trials with a locked safety dataset covering at least 6 months post first vaccine exposure and that were completed before 16 March 2011 defined as the data lock point (DLP) were included. All adults subjects that received the AS03adjuvanted pandemic vaccines (alone or followed with the administration of another study vaccine) and unadjuvanted mono or trivalent influenza control vaccine or placebo in eligible studies were included. Eligible primary vaccination studies include: , , , , , /109873, , , , , , , , , , , , , , , , , and Eligible booster vaccination studies include: , , , , and /111470/111471/ For data concerning those individual studies, please refer to the individual CTRS. This CTRS presents the safety data of all vaccination studies completed before 16 March 2011 (DLP). At that point, data cleaning had been completed for all data following primary vaccinations though not for all booster studies. Study Design: Analyses of safety pooling data from subjects aged 18 years and above, who participated in influenza pandemic studies designed with investigational AS03adjuvanted DPAN and QPAN H5N1 and H1N1 vaccine formulations. Study Population: Adult subjects aged 18 years and above who had participated in an influenza pandemic vaccine study and who had received at least one vaccine dose. The following groups were used for the pooled statistical analyses: : Subjects who received at least 1 one dose of AS03adjuvanted monovalent pandemic influenza H5N1 or H1N1 vaccine. *: Subjects who received at least one dose of an unadjuvanted mono or trivalent influenza vaccine or a placebo in controlled studies where an adjuvanted monovalent pandemic influenza H5N1 and H1N1 vaccine was administered. *For controlled trials only. Study Exposures, Outcomes: The data were collected based on the following study outcomes:

2 Primary outcomes: Occurrence and intensity of any medically attended adverse events (MAEs)* according to the Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms classification Occurrence of any serious adverse events (SAEs) according to the MedDRA ) Preferred Terms classification Occurrence of any potential immunemediated diseases (pimds)** according to the MedDRA ) Preferred Terms classification Occurrence of any adverse events of special interest ()*** according to the MedDRA ) Preferred Terms classification or by Standardized MedDRA Query (SMQ) * MAEs are defined as adverse events (AEs) prompting emergency room (ER) visits, hospitalization or leading to unscheduled visits to medical personal for any reason. ** Potential immunemediated diseases are a subset of AEs that included both clearly autoimmune diseases and other inflammatory and/or neurologic disorders which may or may not have autoimmune etiologies. *** are defined by the Committee for Medicinal Products for Human Use (CHMP) Risk Management Plan for Pandemic Vaccines for safety monitoring. include anaphylaxis, Bell's palsy, convulsion, demyelinating disorders (including multiple sclerosis and optic neuritis), encephalitis, GuillainBarré syndrome, neuritis and vasculitis. Data Analysis Methods: The analyses were performed on the Total Vaccinated cohort, which included all vaccinated subjects who received at least one dose of adjuvanted vaccine or control. The following analyses were performed: Comparative analysis of adjuvanted formulations of the H5N1 and H1N1 vaccines versus control (unadjuvanted mono or trivalent influenza vaccine or placebo), considering Controlled Studies only (primary vaccination only) Safety characterization of adjuvanted formulations of the H5N1 and H1N1 vaccines, based on both Controlled and Uncontrolled Studies (primary vaccination only). Description of any additional identified cases of pimd following a booster vaccination (H5N1 only). Analysis of safety* The analysis for safety was performed on the Total Vaccinated cohort. Personyear incidence rates (per 100,000 personyears) were computed for all events for both the H5N1/H1N1 AS03 and Control groups. The duration of followup (in days) was defined as the time between the date of first vaccination and the date of last data collection. The date of last data collection was either the date the subject completed the last visit or the dropout date. The incidence rate of subjects with at least one report of MAEs classified by the Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms and reported following primary vaccination was tabulated for each group. The same tabulation was performed for grade 3 MAEs. The incidence rate of subjects with at least one report of pimds classified by MedDRA preferred terms was tabulated after primary vaccination for each group. The percentage of subjects with at least one report of classified by MedDRA preferred terms or by narrow SMQ and reported following primary vaccination was tabulated for each group. The incidence rate of subjects with at least one report of SAEs and fatal SAEs classified by MedDRA preferred terms and reported following primary vaccination was tabulated for each group. * Analyses performed for the ISS have taken into account any adverse event reports concerning pimds or in GSK s possession at DLP; At that point, data cleaning had been completed for all data following primary vaccinations though not for all booster studies. The duration of followup for events of interest (MAEs, SAEs, pimds and ) differs across studies. Limitations: Subjects enrolled after 16 March 2011 in any of the ongoing studies did not contribute to the analyses. Any event occurring after 16 March 2011 was not included in this analysis. The number of subjects (N) may vary in the different tables as not all the outcomes have been collected for each study. Study Results: Controlled Studies Demographic/Baseline Characteristics: Enrolled, N (Total Vaccinated cohort) Mean age, years (SD) 44.1 (18.30) 44.8 (18.58) Females: Males 7621: :2735 White Caucasian / European heritage, n (%) (84.1) 5510 (86.6) Controlled and Uncontrolled Studies Demographic/Baseline Characteristics:

3 Enrolled, N (Total Vaccinated cohort) Mean age, years (SD) 44.0 (18.06) Females: Males 9103:7057 White Caucasian / European heritage, n (%) (83.2) Booster Studies* H5N1 AS03 Group Enrolled, N (Total Vaccinated cohort) *Many of these subjects are also included in safety assessments following primary vaccination to time of booster vaccination Primary Efficacy Results: Incidence rate (per 100,000 personyears) of subjects with MAEs in both AS03adjuvanted vaccine and Control groups after first vaccination, based on Controlled Studies only (Total Vaccinated cohort) (H5N1 and H1N1) MAEs T= T= Subjects with any MAE(s), n (n/t per 100,000) 3208 ( ) 1931 ( ) Subjects with grade 3 MAE(s), n (n/t per 100,000) 643 (8632.2) 367 (8361.7) T (years) = total followup time expressed in years n/t = number/incidence rate (per 100,000 personyears) of subjects reporting the MAEs at least once Grade 3 = an adverse event which prevented normal, everyday activities. Primary Efficacy Results: Incidence rate (per 100,000 personyears) of subjects with MAEs in the AS03adjuvanted vaccine group after first vaccination, based on Controlled and Uncontrolled Studies (Total Vaccinated cohort) (H5N1 and H1N1) MAEs T= Subjects with any MAE(s), n (n/t per 100,000) 3742 ( ) Subjects with grade 3 MAE(s), n (n/t per 100,000) 765 (9430.3) T (years) = total followup time expressed in years n/t = number/incidence rate (per 100,000 personyears) of subjects reporting the MAEs at least once Grade 3 = an adverse event which prevented normal, everyday activities. Primary Efficacy Results: Incidence rate (per 100,000 personyears) of subjects with pimds in both AS03adjuvanted vaccine and control groups after first vaccination, based on Controlled Studies only (Total Vaccinated cohort) (H5N1 and H1N1) pimds T= T= Subjects with any pimd(s), n (n/t per 100,000) 31 (350.4) 11 (221.6) T (years) = total followup time expressed in year n/t=number/incidence rate (per 100,000 personyear) of subjects reporting the pimds at least once Primary Efficacy Results: Incidence rate (per 100,000 personyears) of subjects with pimds in the AS03adjuvanted vaccine group after first vaccination, based on Controlled and Uncontrolled Studies (Total Vaccinated cohort) (H5N1 and H1N1) pimds T= Subjects with any pimd(s), n (n/t per 100,000) 38 (351.9) T (years) = total followup time expressed in year n/t=number/incidence rate (per 100,000 personyear) of subjects reporting the pimds at least once Primary Efficacy Results: Number (percentage) of subjects with pimds in both AS03adjuvanted vaccine and control groups following booster vaccination, in Booster Studies only (Total Vaccinated cohort) (H5N1 and H1N1) pimds N=2978 Subjects with any pimd(s), n (%) 6 (0.2) 1 (0.4) VIIth nerve paralysis 1 (0.0) N= 230

4 IIIrd nerve paralysis 1 (0.0) Optic neuritis 1 (0.0) Systemic lupus erythematosus 1 (0.0) Autoimmune thyroiditis 1 (0.0) Multiple sclerosis 1 (0.0) Psoriasis 1 (0.4) : pimd absent Primary Efficacy Results: Incidence rate (per 100,000 personyears) of subjects with in both AS03adjuvanted vaccine and control groups after first vaccination, based on Controlled Studies only, classified by MedDRA preferred terms (Total Vaccinated cohort) (H5N1 and H1N1) T= T= Subjects with any AESI(s), n (n/t per 100,000) 203 (2294.7) 86 (1732.6) T(years) = total followup time expressed in years n/t = number/incidence rate (per 100,000 personyears) of subjects reporting the at least once Primary Efficacy Results: Incidence rate (per 100,000 personyears) of subjects with in the AS03adjuvanted vaccine group after first vaccination, based on Controlled and Uncontrolled Studies, classified by MedDRA preferred terms (Total Vaccinated cohort) (H5N1 and H1N1) T= Subjects with any AESI(s), n (n/t per 100,000) 245 (2269.1) T(years) =total followup time expressed in years n/t = number/incidence rate (per 100,000 personyears) of subjects reporting the at least once Primary Efficacy Results: Incidence rate (per 100,000 personyears) of subjects with in both AS03adjuvanted vaccine and control groups after first vaccination, based on Controlled Studies only, classified by narrow SMQ (Total Vaccinated cohort) (H5N1 and H1N1) T= T= Subjects with any AESI(s), n (n/t per 100,000) 76 (859.1) 24 (483.5) T(years) = total followup time expressed in years n/t = number/incidence rate (per 100,000 personyears) of subjects reporting the at least once Primary Efficacy Results: Incidence rate (per 100,000 personyears) of subjects with in the AS03adjuvanted vaccine group after first vaccination, based on Controlled and Uncontrolled Studies, classified by narrow SMQ (Total Vaccinated cohort) (H5N1 and H1N1) T= Subjects with any AESI (s), n (n/t per 100,000) 86 (796.5) T(years) = total followup time expressed in years n/t = number/incidence rate (per 100,000 personyears) of subjects reporting the at least once Safety Results: Incidence rate (per 100,000 personyears) of subjects with SAEs in both AS03adjuvanted vaccine and control groups after first vaccination, based on Controlled Studies only (Total Vaccinated cohort) (H5N1 and H1N1) SAEs T= T= Subjects with any SAE(s), n (n/t per 100,000) 388 (3598.3) 189 (3662.1) Fatal SAEs T= T=5161.0

5 Subjects with any fatal SAE(s), n (n/t per 100,000) 18 (166.9) 9 (174.4) T(years) = total followup time expressed in years n/t = number/incidence rate (per 100,000 personyears) of subjects reporting the SAEs at least once Safety Results: Incidence rate (per 100,000 personyears) of subjects with SAEs in the AS03adjuvanted vaccine group after first vaccination, based on Controlled and Uncontrolled Studies (Total Vaccinated cohort) (H5N1 and H1N1) SAEs T= Subjects with any SAE(s), n (n/t per 100,000) 507 (3918.3) Fatal SAEs T= Subjects with any fatal SAE(s), n (n/t per 100,000) 22 (170.0) T(years) = total followup time expressed in years n/t = number/incidence rate (per 100,000 personyears) of subjects reporting the SAEs at least once Conclusion: The total safety database for the primary immunization series consisted of subjects 18 years of age and older, of whom subjects received either AS03adjuvanted H5N1 or H1N1 vaccine and 6361 subjects received a control test article. MAEs: Controlled studies included subjects vaccinated with an AS03adjuvanted H5N1 or H1N1 vaccine and 6361 subjects vaccinated with a control test article, corresponding to a total followup time expressed in years of and for MAEs, respectively. Over the period of followup, 3208 subjects in the and 1931 subjects in the reported at least one MAE after first vaccination. The incidence rates of MAEs per 100,000 personyears were in the and in the. During the same period, 643 subjects in the and 367 subjects in the reported grade 3 MAEs. The incidence rates of MAEs per 100,000 personyears were in the and and the Control group. pimds: Controlled studies included subjects vaccinated with an AS03adjuvanted H5N1 or H1N1 vaccine and 6361 subjects vaccinated with a control test article corresponding to a total followup time expressed in years of and for pimds, respectively. Over the period of followup, 31 subjects in the and 11 subjects in the reported at least one pimd after first vaccination. The incidence rates of pimds per 100,000 personyears were in the and in the. : Controlled studies included subjects vaccinated with an AS03adjuvanted H5N1 or H1N1 vaccine and 6361 subjects vaccinated with a control test article corresponding to a total followup time expressed in years of and for, respectively. Over the period of followup, 203 subjects in the and 86 subjects in the reported at least one AESI classified by MedDRA preferred terms, after first vaccination. The incidence rates of per 100,000 personyears were in the and in the. SAEs: Controlled studies included subjects vaccinated with an AS03adjuvanted H5N1 or H1N1 vaccine and 6361 subjects vaccinated with a control test article corresponding to a total followup time expressed in years of and for SAEs, respectively. Over the period of followup, 388 subjects in the and 189 subjects in the reported at least one SAE after first vaccination. The incidence rate of SAEs per 100,000 personyears was in the and in the. Fatal SAEs: Controlled studies included subjects vaccinated with AS03adjuvanted H5N1 or H1N1 vaccine and 6361 subjects vaccinated with a control test article corresponding to a total followup time expressed in years of and for fatal SAEs, respectively. Over the period of followup, 18 subjects in the and 9 subjects in the

6 reported at least one fatal SAE after first vaccination. The incidence rate of fatal SAEs per 100,000 personyears was in the H5N1/H1N1 AS0 Group and in the. The total safety database for the booster immunization series consisted of 3208 subjects of whom 2978 subjects received either AS03adjuvanted H5N1 or H1N1 vaccine and 230 subjects received a control test article. In Booster Studies, following booster vaccination, pimds were reported by 6 subjects in the and by 1 subject in the. Publications: No publications Date Updated: 08November2012