Persistence Study of GSK Biologicals' Tdap Vaccine 1, 3, 5 and 9 Years Following Administration as an Initial Single Dose in Healthy Young Adults and to Evaluate the Immunogenicity and Safety of Boostrix as a Second Dose of Tdap, When Administered at Year 9

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the persistence of antibodies against all the vaccine antigens 1, 3, 5 and 9 years after an initial vaccination with Tdap, and also to assess immunogenicity and safety of another dose of Boostrix, administered in this study. This protocol posting deals with objectives and outcome measures of the extension phase. The objectives and outcome measures of the primary phase are presented in a separate protocol posting (NCT number = NCT00346073).

Detailed Description
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Subjects were previously vaccinated with either Boostrix or a control Tdap vaccine (Sanofi Pasteurs' Adacel) in study NCT00346073. Only subjects who were part of the primary study will be invited to participate in this study. All subjects will receive a single dose of Boostrix at Visit 6 (Day 0) and subjects will be observed till Visit 7 (Day 30) for safety in terms of solicited adverse events (during 4 days post vaccination), unsolicited adverse events (during 31 days post vaccination) and serious adverse event (during the trial period). A blood sample will be collected from all subjects before vaccination (Visit 6) and one month after vaccination (Visit 7) for antibodies estimation. This summary has been updated following Protocol amendment 1 dated 09 November 2010, amendment 2 dated 18 February 2014, and amendment 3 dated 10 December 2014. The protocol was amended first due to the following reasons: The maximum window period allowed for the return of subjects for the Year 5 and Year 10 follow-up visits (Visit 5 and Visit 6) was extended from ± 5 weeks to ± 8 weeks. The contact details for reporting of SAEs were clarified. Text pertaining to the reporting of spontaneous abortion was removed from the protocol. The number of attempts to contact subjects who did not return for scheduled persistence visits was clarified. The main purpose of protocol amendment 2 is to evaluate the immunogenicity and safety of Boostrix as a second dose of Tdap vaccine when administered 8 years after an initial dose of Tdap. The Year 10 time point for evaluation of persistence has been cancelled because it is no longer feasible to conduct after a second dose of Tdap vaccine has been administered at Year 8. The purpose of amendment 3 is to add co-primary objective to demonstrate that the immune response elicited by a second dose of Tdap vaccine, Boostrix (Boostrix group and Adacel group) is non-inferior to the immune response elicited by a first dose of Tdap vaccine (Control group), with respect to booster response against diphtheria, tetanus and pertussis (PT, FHA and PRN) antigens, one month following vaccination according to CBER's input. Accordingly, the study start has been pushed to Year 9 and this is reflected throughout the document.

Official Title
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Persistence Study of GSK Biologicals' Tdap Vaccine (776423), 1, 3, 5 and 9 Years Following Administration as a Single Dose in NCT00346073 Study and to Evaluate the Immunogenicity and Safety of Boostrix as a Second Dose of Tdap, When Administered at Year 9

Conditions
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Acellular Pertussis, Tetanus, Diphtheria

Intervention / Treatment
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* Procedure: Taking of blood samples
* Biological: Boostrix
* Biological: Adacel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: • Persistence follow-up phase up to Year 9 time point: The following criteria are applicable to subjects who refuse vaccination at Year 8 time point: All subjects who received study vaccination (Boostrix or Adacel) in study NCT00346073 will be considered eligible to participate in this study. Written informed consent must be obtained from the subject prior to each study time point. Vaccination phase at Year 9 applicable for subjects in Boostrix and Adacel groups only: The following criterion is applicable to subjects willing to consent to vaccination at Year 9 time point in the Boostrix and Adacel groups: • All subjects who received study vaccination (Boostrix or Adacel) in study NCT00346073 will be considered eligible to participate in this study. Vaccination phase at Year 9 applicable for subjects in the Control group only: The following criterion is applicable to subjects willing to consent to vaccination at Year 9 time point in the Control group only: • Subjects within the age range of 28-73 years will be considered eligible to participate in this study in the Control group. Vaccination phase at Year 9 applicable for ALL subjects (Control, Boostrix and Adacel groups): The following criteria are applicable to subjects willing to consent to vaccination at Year 9 time point in the Boostrix, Adacel and Control groups: All subjects must satisfy the following criteria at study entry at Year 9 time point: Subjects who, in the opinion of the investigator, can and will comply with the requirements of the protocol (e.g. completion of the diary cards, return for follow-up visits). Written informed consent obtained from the subject for vaccination at Year 9 time point. Healthy subjects as established by medical history and clinical examination before entering into the study. Female subjects of non-childbearing potential may be enrolled in the study. Non-childbearing potential is defined as pre-menarche, current tubal ligation, hysterectomy, ovariectomy or post-menopause. Female subjects of child bearing 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 vaccination, and has agreed to continue adequate contraception for 1 month after completion of the vaccine dose Exclusion Criteria: The following criteria should be checked at the time of Year 9 vaccination time point. If any criteria is applicable, the subject must not be vaccinated in the study: For subjects in Boostrix and Adacel groups: • Administration of Tdap vaccine since the last dose received in the study NCT00346073. For subjects in the Control group: • Administration of Tdap (Boostrix or Adacel) vaccine at any time prior to the administration of Boostrix vaccine in this study. For ALL subjects (Control, Boostrix and Adacel groups): Use of any investigational or non-registered product other than the study vaccine within 30 days preceding the dose of study vaccine, or planned use during the study period, 31 days (Day 0-30). Chronic administration (defined as more than 14 days in total) of immunosuppressants or other immune-modifying drugs within six months prior to Visit 6 (pre-vacc). Inhaled and topical steroids are allowed. Planned administration/administration of a vaccine not foreseen by the study protocol in the period starting 30 days before and ending 30 days after the dose of vaccine, with the exception of inactivated Influenza vaccine which is allowed throughout the study period, 31 days (Day 0-30). -- Concurrently participating in another clinical study, at any time during the study period, in which the subject has been or will be exposed to an investigational or a non-investigational vaccine/product. Hypersensitivity to latex. History of diphtheria, tetanus or pertussis diseases. Severe allergic reaction (e.g. anaphylaxis) after previous administration of any tetanus toxoid, diphtheria toxoid, or pertussis-antigen containing vaccines, or any component of Boostrix. History of any neurological disorders or seizures. Encephalopathy (e.g. coma, decreased level of consciousness, prolonged seizures) of unknown etiology occurring within seven days following previous vaccination with pertussis-containing vaccine. Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination (no laboratory testing required). Acute disease and/or fever at the time of enrolment. Fever is defined as temperature ≥ 100.4°F by any route. The preferred route for recording temperature in this study will be oral. Subjects with a minor illness (such as mild diarrhea, mild upper respiratory infection) without fever may, be enrolled at the discretion of the investigator. Administration of immunoglobulins and/or any blood products within three months preceding the dose of study vaccine or planned administration during the study period, 31 days (Day 0-30). Administration of any tetanus or diphtheria containing vaccine or any registered or investigational vaccine utilizing a diphtheria toxoid or tetanus toxoid carrier within 5 years prior to the administration of Boostrix vaccine in this study. Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality, as determined by physical examination or laboratory screening tests. Pregnant or lactating female. Female planning to become pregnant or planning to discontinue contraceptive precautions during the 31 day (Day 0-30) follow-up period post-vaccination.

Ages Eligible for Study
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Minimum Age: 28 Years
Maximum Age: 73 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Boostrix Group<br>Subjects received in the primary study (NCT00346073) a single dose of Boostrix vaccine [Tdap](GSK776423) intramuscularly in the deltoid region of the non-dominant upper arm and in this study at Year 9 received a second dose of Boostrix vaccine [Tdap](GSK776423). | Procedure: Taking of blood samples<br>* No treatment is planned to be given in this study. Blood samples will be collected at the following time points: 1 year, 3 years, 5 years and 9 years after the dose of vaccination.<br>Biological: Boostrix<br>* A single dose of Boostrix was administered in the primary study (NCT00346073). No treatment was given in this study.<br>|
| Active Comparator: Adacel Group<br>Subjects received in the primary study (NCT00346073) a single dose of Adacel vaccine intramuscularly in the deltoid region of the non-dominant upper arm and in this study at Year 9 received a dose of Boostrix vaccine [Tdap](GSK776423). | Procedure: Taking of blood samples<br>* No treatment is planned to be given in this study. Blood samples will be collected at the following time points: 1 year, 3 years, 5 years and 9 years after the dose of vaccination.<br>Biological: Boostrix<br>* A single dose of Boostrix was administered in the primary study (NCT00346073). No treatment was given in this study.<br>Biological: Adacel<br>* A single dose of Adacel was administered in the primary study (NCT00346073). No treatment was given in this study.<br>|
| Active Comparator: Control group<br>Subjects received the first dose of Boostrix vaccine [Tdap](GSK776423) in this study at Year 9. | Biological: Boostrix<br>* A single dose of Boostrix was administered in the primary study (NCT00346073). No treatment was given in this study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Anti-diphtheria (Anti-D) Antibody Concentrations Greater Than or Equal to (≥) Protocol Specified Cut-off | Anti-D cut-off was defined as ≥ 0.1 International Units per milliliter (IU/mL) determined with Enzyme-linked Immunosorbent Assay (ELISA) | At year 1 after the vaccination in primary study (NCT00346073) | 
| Number of Subjects With Anti-D Antibody Concentrations ≥ Protocol Specified Cut-off | Anti-D cut-off was defined as ≥ 0.1 IU/mL as assessed by ELISA | At year 3 after the vaccination in primary study (NCT00346073) | 
| Number of Subjects With Anti-D Antibody Concentrations ≥ Protocol Specified Cut-off | Anti-D cut-off was defined as ≥ 0.1IU/mL as assessed by ELISA. | At year 5 after the vaccination in primary study (NCT00346073) | 
| Number of Subjects With Anti-D Antibody Concentrations ≥ Protocol Specified Cut-off | Anti-D cut-off was defined as ≥ to 0.1IU/mL as assessed by ELISA. | At Year 9, one month before the booster vaccination. | 
| Number of Subjects With Anti-tetanus (Anti-T) Antibody Concentrations ≥ Protocol Specified Cut-off | Anti-T cut-off was defined as ≥ 0.1 IU/mL as assessed by ELISA. | At year 1 after the vaccination in primary study (NCT00346073) | 
| Number of Subjects With Anti-T Antibody Concentrations ≥ Protocol Specified Cut-off | Anti-T cut-off was defined as ≥ 0.1 IU/mL as assessed by ELISA. | At year 3 after the vaccination in primary study (NCT00346073) | 
| Number of Subjects With Anti-T Antibody Concentrations ≥ Protocol Specified Cut-off | Anti-T cut-off was defined as ≥ 0.1 IU/mL as assessed by ELISA. | At year 5 after the vaccination in primary study (NCT00346073) | 
| Number of Subjects With Anti-T Antibody Concentrations ≥ Protocol Specified Cut-off | Anti-T cut-off was defined as ≥ 0.1 IU/mL as assessed by ELISA. | At Year 9, one month before the booster vaccination. | 
| Number of Subjects With Anti-D and Anti-T Concentrations ≥ 0.1 IU/mL and 1 IU/mL | Number of subjects with anti-D and anti-T concentrations ≥ 0.1 IU/mL and 1 IU/mL were tabulated | At Year 9, one month after the booster vaccination. | 
| Anti-pertussis Toxoid (Anti-PT), Anti-filamentous Hemagglutinin (Anti-FHA) and Anti-pertactin (Anti-PRN) Antibody Concentrations | Anti-PT, anti-FHA and anti-PRN antibody concentrations were measured by ELISA, tabulated as GMCs and expressed in IU/mL. | At Year 9, one month before booster vaccination | 
| Anti-pertussis Toxoid (Anti-PT), Anti-filamentous Hemagglutinin (Anti-FHA) and Anti-pertactin (Anti-PRN) Antibody Concentrations | Anti-PT, anti-FHA and anti-PRN antibody concentrations were measured by ELISA, tabulated as GMCs and expressed in IU/mL. | At Year 9, one month after the booster vaccination | 
| Booster Response to D and T Antigens | A booster response was defined as: for initially seronegative subjects (S-) (pre-vaccination concentration below cut-off: < 0.1 IU/mL) antibody concentrations at least four times the cut-off (post vaccination concentration ≥ 0.4 IU/mL); for initially seropositive subjects (S+) (pre-vaccination concentration ≥ 0.1 IU/mL): an increase in antibody concentrations of at least four times the pre-vaccination concentration; Total = subjects either seropositive or seronegative. | At Year 9, one month after the booster vaccination. | 
| Booster Response to PT, FHA and PRN Antigens | Booster response was defined as: for subjects with pre-vaccination antibody concentration < 5 EL.U/mL (S-): antibody concentration ≥ 20 EL.U/mL; for subjects with pre-vaccination antibody concentration ≥ 5 EL.U/mL and < 20 EL.U/mL (S+, <4*cut-off): antibody concentration at least four times the pre-vaccination concentration; for subjects with pre-vaccination antibody concentration ≥ 20 EL.U/mL (S+, ≥4*cut-off): antibody concentration at least two times the pre-vaccination concentration; Total = subjects either seropositive or seronegative | At Year 9, one month after the booster vaccination. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Anti-pertussis Toxoid (PT) Antibody Concentrations Equal to or Above Protocol Specified Cut-off | The cut-off for anti-PT concentrations was defined as ≥ 5 ELISA units per mililiter (EL.U/mL). | At 1, 3, and 5 years after the vaccination in primary study (NCT00346073) | 
| Number of Subjects With Anti-PT Antibody Concentrations Equal to or Above Protocol Specified Cut-off | The cut-off for anti-PT concentrations was defined as equal to or greater than 2.693 IU/mL. | At Year 9, one month before(pre booster) and after the booster vaccination(post booster) | 
| Number of Subjects With Anti-FHA Antibody Concentrations Equal to or Above Protocol Specified Cut-off | The cut-off for anti-FHA concentrations was defined as equal to or greater than 5 EL.U/mL. | At 1, 3, and 5 years after the vaccination in primary study (NCT00346073) | 
| Number of Subjects With Anti-FHA Antibody Concentrations Equal to or Above Protocol Specified Cut-off | The cut-off for anti-FHA concentrations was defined as equal to or greater than 2.046 IU/mL | At Year 9, one month before(pre booster) and after the booster vaccination(post booster) | 
| Number of Subjects With Anti-PRN Antibody Concentrations Equal to or Above Protocol Specified Cut-off | The cut-off for anti-PRN concentrations was defined as equal to or greater than 5 EL.U/mL. | At 1, 3, and 5 years after the vaccination in primary study (NCT00346073) | 
| Number of Subjects With Anti-PRN Antibody Concentrations Equal to or Above Protocol Specified Cut-off | The cut-off for anti-PRN concentrations was defined as equal to or greater than 2.187 IU/mL. | At Year 9, one month before(pre booster) and after the booster vaccination(post booster) | 
| Anti-D Antibody Concentration | Anti-D antibody concentration is expressed as geometric mean concentration (GMC) in IU/mL. | At 1, 3, and 5 years after the vaccination in primary study (NCT00346073) | 
| Anti-D Antibody Concentration | Anti-D antibody concentration is expressed as GMC in IU/mL. | At Year 9, one month before(pre booster) and after the booster vaccination(post booster) | 
| Anti-T Antibody Concentration | Anti-T antibody concentration is expressed as GMC in IU/mL. | At 1, 3, and 5 years after the vaccination in primary study (NCT00346073) | 
| Anti-T Antibody Concentration | Anti-T antibody concentration is expressed as GMC in IU/mL. | At Year 9, one month before(pre booster) and after the booster vaccination(post booster) | 
| Anti-PT Antibody Concentration | Anti-PT antibody concentration is expressed as GMC in EL.U/mL. | At 1, 3, and 5 years after the vaccination in primary study (NCT00346073) | 
| Anti-PT Antibody Concentration | Anti-PT antibody concentration was expressed as GMC in IU/mL. | At Year 9, one month before(pre booster) and after the booster vaccination(post booster) | 
| Anti-FHA Antibody Concentration | Anti-FHA antibody concentration is expressed as GMC in IU/mL | At 1, 3, and 5 years after the vaccination in primary study (NCT00346073) | 
| Anti-FHA Antibody Concentration | Anti-FHA antibody concentration was expressed as GMC in IU/mL. | At Year 9, one month before(pre booster) and after the booster vaccination(post booster) | 
| Anti-PRN Antibody Concentration | Anti-PRN antibody concentration is expressed as GMC in IU/mL | At 1, 3, and 5 years after the vaccination in primary study (NCT00346073) | 
| Anti-PRN Antibody Concentration | Anti-PRN antibody concentration is expressed as GMC in IU/mL. | At Year 9, one month before(pre booster) and after the booster vaccination(post booster) | 
| Alternative Booster Response to Anti-D and Anti-T Antigens | Alternative Booster response to D and T antigens is defined as: - For subjects with pre-booster antibody concentration below 0.1 IU/mL: antibody concentrations at least four times the 0.1IU/ML, one month after vaccination, and - For subjects with pre-booster antibody concentration ≥0.1 IU/mL and <1.0 IU/mL: antibody concentrations of at least four times the pre-booster antibody concentration, one month after vaccination. - For subjects with pre-booster antibody concentration ≥1.0 IU/mL and <6.0 IU/mL: antibody concentrations of at least two times the pre-booster antibody concentration, one month after vaccination. - Subjects with pre-booster antibody concentration ≥6.0 IU/mL are not evaluable for booster response. S- = Antibody concentration < 0.1 IU/mL S+ = Antibody concentration ≥ 0.1 IU/mL Total = subjects either seropositive or seronegative | At Year 9, one month after booster vaccination | 
| Alternative Booster Responses to Anti-PT, Anti-FHA and Anti-PRN Antigens | Alternative Booster response to PT, FHA and PRN antigens is defined as: - For subjects with pre-booster antibody concentration below the assay cut off: antibody concentrations at least four times the assay cut off one month after vaccination, and - For subjects with pre-booster antibody concentration ≥ assay cut off and < 60 IU/mL: antibody concentration increase of at least 30 IU/mL from the pre-booster antibody concentration, one month after vaccination. - For subjects with pre-booster antibody concentration ≥ 60 IU/mL : at least 1.5 fold increase of antibody concentration from the pre-booster antibody concentration, one month after vaccination. S- = seronegative subjects (antibody concentration below assay cut off for anti-PT, anti-FHA, anti-PRN) S+ = seropositive subjects (antibody concentration below assay cut off for anti-PT, anti-FHA, anti-PRN) Total = subjects either seropositive or seronegative | At Year 9, one month after booster vaccination | 
| Seroprotection Status for Anti-D Antibody Concentration | Seroprotection status for anti-D antibody concentration < 0.1 IU/mL were tested for neutralizing antibodies using a VERO-cell neutralization assay. Seroprotection rate is defined as the percentage of subjects with antibody concentrations greater than or equal (≥) the seroprotection cut-off value defined for that antibody. | At Year 9, one month before(pre booster) and after the booster vaccination(post booster) | 
| Number of Subjects With Any and Grade 3 Solicited Local Symptoms - Year 9 | Solicited local symptoms assessed were pain, redness and swelling. Any was defined as any solicited local symptom reported irrespective of intensity. Grade 3 pain was defined as significant pain at rest that prevented normal everyday activities. Grade 3 redness and swelling was greater than 50 millimeters (mm) | During the 4-day (Days 0-3) post vaccination period. | 
| Number of Subjects With Any, Grade 3 and Related Solicited General Symptoms - Year 9 | The solicited general symptoms assessed were Fatigue, Gastrointestinal symptoms (including nausea, vomiting, diarrhea and abdominal pain), Headache and Fever [defined as temperature of ≥100.4 degrees Fahrenheit (F) by any route]. Any = Occurrence of any general symptom regardless of its intensity grade or relationship to vaccination; Grade 3 Symptom = Symptom that prevented normal activity; Grade 3 Fever > 104.0 degrees F. | During the 4-day (Days 0-3) post vaccination period. | 
| Number of Subjects With Any Large Injection Site Reaction - Year 9 | Large injection site reaction = a swelling with a diameter > 100 mm, noticeable diffuse swelling or noticeable increase in limb circumference. | During the 4-day (Days 0-3) follow-up period after vaccination. | 
| Number of Subjects With Any Unsolicited Adverse Events (AEs) - Year 9 | An unsolicited AE covers any untoward medical oc-currence 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. | During the 31-day (Days 0-30) post-vaccination period. | 
| Number of Subjects With Serious Adverse Events (SAEs) - Year 9 | SAEs assessed include medical occurrences that result in death, are life-threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity. | During the 31-day (Days 0-30) post-vaccination period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Persistence, immunogenicity