Safety and Immunogenicity of H1N1 Vaccines in Adults Aged 18 Years and Older

Phase 2

Completed

Conditions: Influenza

Interventions: Biological: GSK2340274A
Biological: GSK2340273A
Biological: Saline placebo

Registration Number: NCT00985088

Lead Sponsor: GlaxoSmithKline

Brief Summary: The purpose of this study is to characterize the safety and immunogenicity of the H1N1 (swine) flu vaccines GSK2340273A and GSK2340274A in adults 18 years of age or older.

This protocol posting has been updated for sections impacted by the Protocol amendment 1, Sept 2009.

Detailed Description: Collaborators: United States Department of Health and Human Services, Office of Biomedical Advanced Research and Development Authority

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 1343

Inclusion Criteria

Subjects who the investigator believes can and will comply with the requirements of the protocol.
Written informed consent obtained from the subject.
Male and female adults, >= 18 years of age at the time of the first vaccination.
Safety laboratory test results within the parameters specified in the protocol.
Satisfactory baseline medical assessment by history and physical examination.
Comprehension of the study requirements, ability to comprehend and comply with procedures for collection of safety data, expressed availability for the required study period, and ability and willingness to attend scheduled visits as documented by signature on the informed consent document.
Access to a consistent means of telephone contact, which may be either in the home or at the workplace, land line or mobile, but NOT a pay phone or other multiple-user device.
Female subjects of non-childbearing potential may be enrolled in the study.
Female subjects of childbearing potential may be enrolled in the study, if the subject:
has practiced adequate contraception for 30 days prior to vaccination, and
has a negative pregnancy test on the day of first vaccination, and
has agreed to continue adequate contraception during the entire treatment period and for 2 months after completion of the vaccination series.

Exclusion Criteria

Medical history of physician-confirmed infection with an A/California/7/2009 (H1N1)v-like virus
Previous vaccination at any time with an H1N1v-like virus vaccine or a medical history of physician-confirmed infection with an H1N1v-like virus.
Presence of evidence of substance abuse or of neurological or psychiatric diagnoses which, even if stable, are deemed by the investigator to render the potential subject unable/unlikely to provide accurate safety reports.
Presence of a temperature >= 38.0ºC (>=100.4ºF), or acute symptoms greater than "mild" severity on the scheduled date of first vaccination.
Diagnosed with cancer, or treatment for cancer, within 3 years.
Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination (no laboratory testing required).
Receipt of systemic glucocorticoids within 1 month prior to study enrollment, or any other cytotoxic or immunosuppressive drug within 6 months of study enrollment. Topical, intra-articularly injected, or inhaled glucocorticoids, topical calcineurin inhibitors or imiquimod are allowed.
Receipt of any immunoglobulins and/or any blood products within 3 months of study enrollment or planned administration of any of these products during the study period.
Any significant disorder of coagulation or treatment with warfarin derivatives or heparin. Persons receiving individual doses of low molecular weight heparin outside of 24 hours prior to vaccination, are eligible. Persons receiving prophylactic antiplatelet medications, e.g., low-dose acetylsalicylic acid, and without a clinically-apparent bleeding tendency, are eligible.
An acute evolving neurological disorder or history of Guillain-Barré syndrome within 6 weeks of receipt of seasonal influenza vaccine
With the exception of seasonal influenza vaccination, administration of any vaccine(s) within 30 days before study vaccination on Day 0. Seasonal influenza vaccine may be administered up to 14 days prior to study vaccination on Day 0.
Planned administration of any vaccine not foreseen by the study protocol between Day 0 and the Day 42 phlebotomy, including seasonal influenza vaccine or a monovalent pandemic H1N1 vaccine other than the study vaccines.
Use of any investigational or non-registered product (drug or vaccine) other than the study vaccine(s) within 30 days preceding the first dose of study vaccine/product, or planned use during the study period.
Any known or suspected allergy to any constituent of influenza vaccines; a history of anaphylactic-type reaction to any constituent of influenza vaccines; or a history of severe adverse reaction to a previous influenza vaccine.
Known pregnancy or a positive urine beta-human chorionic gonadotropin test result prior to the first vaccination.
Lactating or nursing women.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
GSK2340274A F1_2D Group	GSK2340274A	Healthy male or female subjects, above and including 18 years of age, who received 2 doses of Formulation 1 (F1) of GSK2340274A vaccine: at Day 0, administered intramuscularly into the deltoid region of the non-dominant arm and at Day 21, administered intramuscularly into the deltoid region of the dominant arm.
GSK2340273A F3_2D Group	GSK2340273A	Healthy male or female subjects, above and including 18 years of age, who received 2 doses of Formulation 3 of GSK2340273A vaccine: at Day 0, administered intramuscularly into the deltoid region of the non-dominant arm and at Day 21, administered intramuscularly into the deltoid region of the dominant arm.
GSK2340274A F2_2D Group	GSK2340274A	Healthy male or female subjects, above and including 18 years of age, who received 2 doses of Formulation 2 (F2) of GSK2340274A vaccine: at Day 0, administered intramuscularly into the deltoid region of the non-dominant arm and at Day 21, administered intramuscularly into the deltoid region of the dominant arm.
GSK2340274A F2_1D Group	Saline placebo	Healthy male or female subjects, above and including 18 years of age, who received one dose of Formulation 2 (F2) of GSK2340274A vaccine at Day 0, administered intramuscularly into the deltoid region of the non-dominant arm and one dose of saline placebo at Day 21, administered intramuscularly into the deltoid region of the dominant arm.
GSK2340273A F2_1D Group	GSK2340273A	Healthy male or female subjects, above and including 18 years of age, who received one dose of Formulation 2 (F2) of GSK2340273A vaccine at Day 0, administered intramuscularly into the deltoid region of the non-dominant arm and one dose of saline at Day 21, administered intramuscularly into the deltoid region of the dominant arm. Subjects above (\>) 60 years old received an additional dose of Formulation 2 (F2) of GSK2340273A vaccine after Day 42, administered into the deltoid region of the non-dominant arm.
GSK2340274A F2_1D Group	GSK2340274A	Healthy male or female subjects, above and including 18 years of age, who received one dose of Formulation 2 (F2) of GSK2340274A vaccine at Day 0, administered intramuscularly into the deltoid region of the non-dominant arm and one dose of saline placebo at Day 21, administered intramuscularly into the deltoid region of the dominant arm.
GSK2340273A F1_1D Group	GSK2340273A	Healthy male or female subjects, above and including 18 years of age, who received one dose of Formulation 1 (F1) of GSK2340273A vaccine at Day 0, administered intramuscularly into the deltoid region of the non-dominant arm and one dose of saline at Day 21, administered intramuscularly into the deltoid region of the dominant arm.
GSK2340273A F1_1D Group	Saline placebo	Healthy male or female subjects, above and including 18 years of age, who received one dose of Formulation 1 (F1) of GSK2340273A vaccine at Day 0, administered intramuscularly into the deltoid region of the non-dominant arm and one dose of saline at Day 21, administered intramuscularly into the deltoid region of the dominant arm.
GSK2340274A F1_1D Group	GSK2340274A	Healthy male or female subjects, above and including 18 years of age, who received one dose of Formulation 1 (F1) of GSK2340274A vaccine at Day 0, administered intramuscularly into the deltoid region of the non-dominant arm and one dose of saline placebo at Day 21, administered intramuscularly into the deltoid region of the dominant arm.
GSK2340274A F1_1D Group	Saline placebo	Healthy male or female subjects, above and including 18 years of age, who received one dose of Formulation 1 (F1) of GSK2340274A vaccine at Day 0, administered intramuscularly into the deltoid region of the non-dominant arm and one dose of saline placebo at Day 21, administered intramuscularly into the deltoid region of the dominant arm.
GSK2340273A F2_2D Group	GSK2340273A	Healthy male or female subjects, above and including 18 years of age, who received 2 doses of Formulation 2 (F2) of GSK2340273A vaccine: at Day 0, administered intramuscularly into the deltoid region of the non-dominant arm and at Day 21, administered intramuscularly into the deltoid region of the dominant arm.
GSK2340273A F2_1D Group	Saline placebo	Healthy male or female subjects, above and including 18 years of age, who received one dose of Formulation 2 (F2) of GSK2340273A vaccine at Day 0, administered intramuscularly into the deltoid region of the non-dominant arm and one dose of saline at Day 21, administered intramuscularly into the deltoid region of the dominant arm. Subjects above (\>) 60 years old received an additional dose of Formulation 2 (F2) of GSK2340273A vaccine after Day 42, administered into the deltoid region of the non-dominant arm.

Primary Outcome Measures

Name	Time	Method
Seroconversion Factor (SCF) for Haemagglutination Inhibition (HI) Antibodies Against A/California Virus Strain	At Day 21	SCF was defined as the fold increase in serum HI geometric mean ratio (mean\[log10(POST/PRE)\]) vaccination compared to Day 21. The flu strain assessed was Flu A/CAL/7/09 and results were tabulated for subjects between 18 and 60 years of age and older (\>60y).
Number of Subjects Seropositive for (HI) Antibodies Against the A/California Virus Strain	At Day 21	A seropositive subject against the A/California/ virus strain was defined as a subject with H1N1 reciprocal haemagglutination inhibition (HI) antibody titers greater than or equal to (≥) the seropositivity cut-off of 1:10. Results were tabulated according to age strata: subjects between 18 to 64 years (y) old and subjects \> 64 years.
Number of Seroconverted (SCR) Subjects for Haemagglutination Inhibition (HI) Antibodies Against A/California Virus Strain	At Day 21	A seroconverted subject was defined as a vaccinated subject who had a post-vaccination titer ≥ 1:40 and at least a 4-fold increase in pre-vaccination titer. The Flu strain assessed was A/California/7/09 (H1N1)v-like) and results were tabulated for subjects between 18 and 60 years of age and older (\>60y).
Number of Subjects Seropositive for Haemagglutination Inhibition (HI) Antibodies Against the A/California Virus Strain	At Day 21	A seropositive subject against the A/California/ virus strain was defined as a subject with H1N1 reciprocal haemagglutination inhibition (HI) antibody titers greater than or equal to (≥) the seropositivity cut-off of 1:10. Results were tabulated according to age strata: subjects between 18 to 60 years (y) old and subjects \> 60 years.
Number of Seroconverted (SCR) Subjects for HI Antibodies Against A/California Strain	At Day 21	A seroconverted subject was defined as a vaccinated subject who had a post-vaccination titer ≥ 1:40 and at least a 4-fold increase in pre-vaccination titer. The Flu strain assessed was A/California/7/09 (H1N1)v-like) and results were tabulated for subjects between 18 and 64 years and older (\>64y).
Number of Seroprotected (SPR) Subjects for HI Antibodies Against A/California Virus Strain	At Day 21	A seroprotected subject was defined as a vaccinated subject with serum Hemagglutination Inhibition (HI) titer ≥ 1:40. The Flu strain assessed was Flu A/CAL/7/09 and results were tabulated for subjects between 18 and 60 years and older (\>60y).
Number of Seroprotected (SPR) Subjects for HI Antibodies Against A/California Strain	At Day 21	A seroprotected subject was defined as a vaccinated subject with serum Hemagglutination Inhibition (HI) titer ≥ 1:40. The Flu strain assessed was Flu A/CAL/7/09 and results were tabulated for subjects between 18 and 64 years and older (\>64y).
Seroconversion Factor (SCF) for HI Antibodies Against A/California Strain	At Day 21	SCF was defined as the fold increase in serum HI geometric mean ratio (mean\[log10(POST/PRE)\]) vaccination compared to Day 21. The flu strain assessed was Flu A/CAL/7/09 and results were tabulated for subjects between 18 and 64 years of age and older (\>64y).

Secondary Outcome Measures

Name	Time	Method
Titers for HI Antibodies Against A/California Strain	At Days 0 and 21	Antibody titers were presented as geometric mean titers (GMTs), for the seropositivity cut-off of 1:10. Results were tabulated according to age strata: subjects between 18 to 60 years (y) old and \> 60 years and subjects between 18 and 64 years old and \> 64 years, respectively.
Adjusted GMT Ratios for A/California Strain	At Day 21	Titers were presented as geometric mean titers (GMTs). Adjusted GMT was defined as the geometric mean antibody titer adjusted for Previous Vaccination baseline titers and results were tabulated for subjects between 18-60 years, \> 60 years, 18-64 years and \> 64 years, from the pooled group GSK2340274A F2 and the GSK2340273A F1_1D Group.
Number of Subjects Seropositive for HI Antibodies Against A/California Virus Strain	At Days 0 and 21	A seropositive subject against the A/California/ virus strain was defined as a subject with H1N1 reciprocal haemagglutination inhibition (HI) antibody titers greater than or equal to (≥) the seropositivity cut-off of 1:10. Results were tabulated according to age strata: subjects between 18 to 60 years (y) old and \> 60 years and subjects between 18 and 64 years old and \> 64 years, respectively.
Number of Seroconverted (SCR) Subjects for HI Antibodies Against A/California Virus Strain	At Day 42	A seroconverted subject was defined as a vaccinated subject who had a post-vaccination titer ≥ 1:40 and at least a 4-fold increase in pre-vaccination titer. The Flu strain assessed was A/California/7/09 (H1N1)v-like) and results were tabulated for subjects between 18-60 years of age and older (\>60y) and for subjects between 18-64 years old and \>64 years.
Number of Seroprotected (SPR) Subjects Against HI Antibodies for the A/California Virus Strain	At Days 0 and 21	A seroprotected subject was defined as a vaccinated subject with serum HI antibody titers ≥ 1:40. The Flu strain assessed was A/California/7/09 (H1N1)v-like) and results were tabulated for subjects between 18-60 years of age and older (\>60y) and for subjects between 18-64 years old and \>64 years.
Seroconversion Factor (SCF) for HI Antibodies Against A/California Virus Strain	At Day 182	SCF was defined as the fold increase in serum HI geometric mean ratio (mean\[log10(POST/PRE)\]) vaccination compared to Day 21. The flu strain assessed was Flu A/CAL/7/09 and results were tabulated for subjects between 18-60 years of age and older (\> 60y) and for subjects between 18-64 years old and \> 64 years.
Titers for HI Antibodies Against the A/California Virus Strain	At Days 0 and 182	Antibody titers were presented as geometric mean titers (GMTs), for the seropositivity cut-off of 1:10. Results were tabulated according to age strata: subjects between 18 to 60 years (y) old and \> 60 years and subjects between 18 and 64 years old and \> 64 years, respectively.
Adjusted GMT Ratios of A/California Virus Strain	At Day 21	Titers were presented as geometric mean titers (GMTs). Adjusted GMT was defined as the geometric mean antibody titer adjusted for Previous Vaccination baseline titers and results were tabulated for subjects between 18-60 years, \> 60 years, 18-64 years and \> 64 years, from the pooled group GSK2340274A F1 and the GSK2340273A F1_1D Group.
Number of Seroprotected (SPR) Subjects for HI Antibodies Against A/California Virus Strain	At Days 0 and 182	A seroprotected subject was defined as a vaccinated subject with serum HI antibody titers ≥ 1:40. The Flu strain assessed was A/California/7/09 (H1N1)v-like) and results were tabulated for subjects between 18-60 years of age and older (\>60y) and for subjects between 18-64 years old and \>64 years.
Adjusted Geometric Mean Titer (GMT) Ratios of A/California Strain	At Day 21	Titers were presented as geometric mean titers (GMTs). Adjusted GMT was defined as the geometric mean antibody titer adjusted for Previous Vaccination baseline titers and results were tabulated for subjects between 18-60 years, \> 60 years, 18-64 years and \> 64 years, from the pooled groups GSK2340274A F1 and GSK2340273A F2.
Adjusted GMT Ratios of A/California Strain	At Day 21	Titers were presented as geometric mean titers (GMTs). Adjusted GMT was defined as the geometric mean antibody titer adjusted for Previous Vaccination baseline titers and results were tabulated for subjects between 18-60 years, \> 60 years, 18-64 years and \> 64 years, from the pooled group GSK2340274A F2 and the GSK2340273A F3_2D Group.
Number of Subjects With Any and Grade 3 Solicited General Symptoms	During the 7-day (Days 0-6) post-Dose 3 vaccination period, for subjects > 60 years of age	Assessed solicited general symptoms were fatigue, fever \[defined as axillary temperature equal to or above (≥) 38 degrees Celsius (°C)\], headache, joint pain at other location, muscle aches, shivering and sweating. Any = occurrence of the symptom regardless of intensity grade or relationship to vaccination. Grade 3 symptom = symptom that prevented normal everyday activities as assessed by inability to attend/do work or school, or required intervention of a physician/healthcare provider. Grade 3 fever = fever ≥ 39.0 °C. Related = symptom assessed by the investigator as related to the vaccination. Results were tabulated for subjects in GSK2340273A F2_1D Group, who were older than 60 years of age (\>60y).
Number of Subjects With Abnormal Biochemical and Haematological Levels	At Days 7, 21, 28, 42 and 182, for subjects > 64 years of age	Among biochemical and haematological parameters assessed were alanine aminotransferase \[ALT\], alkaline phosphatase \[AP\], aspartate aminotransferase \[AST\], basophils \[BAS\], bilirubin \[BIL\], bilirubin conjugated/direct \[BIL/CD\] creatinine \[CREA\], eosinophils \[EOS\], hematocrit \[HEM\], haemoglobin \[Hgb\], lymphocytes \[LYM\], monocytes \[MON\], neutrophils \[NEU\], platelets \[PLA\], red blood cells \[RBC\], blood urea nitrogen \[BUN\] and white blood cells \[WBC\]. Levels of haematological/biochemical parameters assessed in terms of normal laboratory values were - unknown, below, within and above the reference range defined for the specified time point and laboratory parameter.
Number of Subjects With Any Unsolicited Adverse Events (AEs)	Within the 84-day (Days 0-83) post-vaccination period	An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination. Results were tabulated for subjects aged between 18-64 years and older (\>64y).
Number of Subjects Seropositive for HI Antibodies Against the A/California Virus Strain	At Days 0 and 182	A seropositive subject against the A/California/ virus strain was defined as a subject with H1N1 reciprocal HI antibody titers greater than or equal to (≥) the seropositivity cut-off of 1:10. Results were tabulated according to age strata: subjects between 18 to 60 years (y) old and \> 60 years and subjects between 18 and 64 years old and \> 64 years, respectively.
Number of Seroprotected (SPR) Subjects for HI Antibodies Against A/California Strain	At Days 0 and 42	A seroprotected subject was defined as a vaccinated subject with serum HI antibody titers ≥ 1:40. The Flu strain assessed was A/California/7/09 (H1N1)v-like) and results were tabulated for subjects between 18-60 years of age and older (\>60y) and for subjects between 18-64 years old and \>64 years.
Adjusted GMT Ratios for A/California Virus Strain	At Day 21	Titers were presented as geometric mean titers (GMTs). Adjusted GMT was defined as the geometric mean antibody titer adjusted for Previous Vaccination baseline titers and results were tabulated for subjects between 18-60 years, \> 60 years, 18-64 years and \> 64 years, from the pooled groups GSK2340274A F2 and GSK2340273A F2.
Number of Subjects With Serious Adverse Events (SAEs)	During the entire study period (from Day 0 to Day 385)	Serious adverse events (SAEs) assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity. Results were tabulated for subjects aged between 18-64 years and older (\>64y).
Number of Seroconverted (SCR) Subjects for HI Antibodies	At Day 182	A seroconverted subject was defined as a vaccinated subject who had a post-vaccination titer ≥ 1:40 and at least a 4-fold increase in pre-vaccination titer. The Flu strain assessed was A/California/7/09 (H1N1)v-like) and results were tabulated for subjects between 18-60 years of age and older (\>60y) and for subjects between 18-64 years old and \>64 years.
Adjusted Geometric Mean Titer (GMT) Ratios of A/California Virus Strain	At Day 21	Titers were presented as geometric mean titers (GMTs). Adjusted GMT was defined as the geometric mean antibody titer adjusted for Previous Vaccination baseline titers and results were tabulated for subjects between 18-60 years, \> 60 years, 18-64 years and \> 64 years, from the pooled group GSK2340274A F1 and GSK2340273A F3_2D Group.
Number of Subjects With Any and Grade 3 Solicited Local Symptoms	During the 7-day (Days 0-6) post-Dose 3 vaccination period, for subjects > 60 years of age	Assessed solicited local symptoms were pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade. Grade 3 pain = pain that prevented normal activities as assessed by inability to attend/do work or school. Grade 3 redness/swelling = redness/swelling spreading beyond 100 millimeters (mm) of injection site. Results were tabulated for subjects in GSK2340273A F2_1D Group, who were older than 60 years of age (\>60y).
Number of Subjects With Any, Grade 3 and Related Solicited General Symptoms	During the 7-day (Day 0-6) post-vaccination period following each dose and across doses, for subjects > 64 years of age	Assessed solicited general symptoms were fatigue, fever \[defined as axillary temperature equal to or above (≥) 38 degrees Celsius (°C)\], headache, joint pain at other location, muscle aches, shivering and sweating. Any = occurrence of the symptom regardless of intensity grade or relationship to vaccination. Grade 3 symptom = symptom that prevented normal everyday activities as assessed by inability to attend/do work or school, or required intervention of a physician/healthcare provider. Grade 3 fever = fever ≥ 39.0 °C. Related = symptom assessed by the investigator as related to the vaccination.
Number of Subjects Reporting Any Potential Immune-mediated Diseases (pIMDs)	Days 0 to 365	Potential immune-mediated diseases (pIMDs) are a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune aetiology. Results were tabulated for subjects aged between 18-64 years and above 65 years (+65y).
Number of Subjects With Any Medically-attended Adverse Events (MAEs)	Days 0 to 385	MAEs were defined as events for which the subject received medical attention defined as hospitalization, an emergency room visit, or a visit to or from medical personnel (medical doctor) for any reason. Any was defined as the occurrence of any MAE regardless of intensity grade or relation to vaccination. Results were tabulated for subjects aged between 18 and 64 years and older (\>64y).