Safety and Immunogenicity Study of GSK Biologicals Tuberculosis Vaccines (692342) to Healthy Adults

Study Overview
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Brief Summary
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This observer blind study will assess the safety and immunogenicity of different formulations of GSK Biologicals' 692342 tuberculosis vaccine in healthy adults aged 18 to 45 years with a positive PPD skin test. The Protocol Posting has been updated in order to comply with the FDA Amendment Act, Sep 2007.

Official Title
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Dose Range Study Evaluating Safety and Immunogenicity Study of GSK Biologicals' Candidate Tuberculosis Vaccines (692342) When Administered to Healthy Adults Aged 18 to 45 Years.

Conditions
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Tuberculosis

Intervention / Treatment
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* Biological: GSK Biologicals' AS01B adjuvant
* Biological: GSK Biologicals' Candidate Tuberculosis Vaccine (692342) - Formulation 1
* Biological: GSK Biologicals' Candidate Tuberculosis Vaccine (692342) - Formulation 2
* Biological: GSK Biologicals' Candidate Tuberculosis Vaccine (692342) - Formulation 3
* Biological: GSK Biologicals' Candidate Tuberculosis Vaccine (692342) - Formulation 4 - Dosage 1
* Biological: GSK Biologicals' Candidate Tuberculosis Vaccine (692342) - Formulation 4 - Dosage 2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who the investigator believes that they can and will comply with the requirements of the protocol should be enrolled in the study. A male or female between, and including, 18 and 45 years of age at the time of the first vaccination. Written informed consent obtained from the subject prior to any study procedure. Free of obvious health problems as established by medical history and clinical examination before enrolment into the study. If the subject is female, she must be of non-childbearing potential or if she is of childbearing potential, she must practice adequate contraception for 30 days prior to vaccination, have a negative pregnancy test and continue such precautions for 2 months after completion of the vaccination series. No evidence of pulmonary pathology as confirmed by chest X-ray. No history of extrapulmonary TB. Clinically normal laboratory values for creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST), complete blood count (CBC) and urinalysis. Seronegative for human immunodeficiency virus-1 and -2 (HIV-1 and -2) antibodies. Subjects must have a PPD positive skin reactivity 48 to 72 hours after PPD skin test administration. Exclusion Criteria: Use of any investigational or non-registered product (drug or vaccine) other than the study vaccine within 30 days preceding the first dose of study vaccine, or planned use during the study period. Chronic administration of immunosuppressants or other immune-modifying drugs within six months prior to the first vaccine dose. Any chronic drug therapy to be continued during the study period, with the exception of vitamins and/or dietary supplements, herbal medications, birth control pills, anti-histamines for seasonal allergies and SSRIs. History of previous administration of experimental Mycobacterium tuberculosis vaccines. History of previous exposure to experimental products containing MPL or QS21. Administration of any immunoglobulins, any immunotherapy and/or any blood products within the three months preceding the first dose of study vaccination, or planned administrations during the study period. 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 product (pharmaceutical product or device). Any confirmed or suspected immunosuppressive or immunodeficient condition based on medical history and physical examination. A family history (first generation) of congenital or hereditary immunodeficiency. History of any acute or chronic illness or medication that, in the opinion of the investigator, may interfere with the evaluation of the safety or immunogenicity of the vaccine. History of any neurological disorders or seizures. History of allergic reactions or anaphylaxis to previous immunisations. History of allergic disease or reactions likely to be exacerbated by any component of the vaccine. History of chronic alcohol consumption and/or drug abuse. Major congenital defects. Pregnant or lactating female. Female planning to become pregnant or planning to discontinue contraceptive precautions.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Control Group<br>Healthy adults between and including 18 to 45 years of age at the time of first vaccination, who received 2 doses of the control GSK Biologicals' AS01B adjuvanted system, at Day 0, intramuscularly in the non-dominant arm and at Day 30, intramuscularly in the dominant arm. | Biological: GSK Biologicals' AS01B adjuvant<br>* Intramuscular injection, 2 doses<br>|
| Active Comparator: GSK692342_F1 Group<br>Healthy adults between and including 18 to 45 years of age at the time of first vaccination, who received 2 doses of the non-adjuvanted GSK692342 vaccine formulation 1 (F1), at Day 0, intramuscularly in the non-dominant arm and at Day 30, intramuscularly in the dominant arm. | Biological: GSK Biologicals' Candidate Tuberculosis Vaccine (692342) - Formulation 1<br>* Intramuscular injection, 2 doses<br>|
| Experimental: GSK692342_F2 Group<br>Healthy adults between and including 18 to 45 years of age at the time of first vaccination, who received 2 doses of the adjuvanted GSK692342 vaccine formulation 2 (F2), at Day 0, intramuscularly in the non-dominant arm and at Day 30, intramuscularly in the dominant arm. | Biological: GSK Biologicals' Candidate Tuberculosis Vaccine (692342) - Formulation 2<br>* Intramuscular injection, 2 doses<br>|
| Experimental: GSK692342_F3 Group<br>Healthy adults between and including 18 to 45 years of age at the time of first vaccination, who received 2 doses of the adjuvanted GSK692342 vaccine formulation 3, at Day 0, intramuscularly in the non-dominant arm and at Day 30, intramuscularly in the dominant arm. | Biological: GSK Biologicals' Candidate Tuberculosis Vaccine (692342) - Formulation 3<br>* Intramuscular injection, 2 doses<br>|
| Experimental: GSK692342_F4D1 Group<br>Healthy adults between and including 18 to 45 years of age at the time of first vaccination, who received 2 doses of the adjuvanted GSK692342 vaccine formulation 4 dosage 1 (F4D1), at Day 0, intramuscularly in the non-dominant arm and at Day 30, intramuscularly in the dominant arm. | Biological: GSK Biologicals' Candidate Tuberculosis Vaccine (692342) - Formulation 4 - Dosage 1<br>* Intramuscular injection, 2 doses<br>|
| Experimental: GSK692342_F4D2 Group<br>Healthy adults between and including 18 to 45 years of age at the time of first vaccination, who received 2 doses of the adjuvanted GSK692342 vaccine formulation 4 dosage 2 (F4D2), at Day 0, intramuscularly in the non-dominant arm and at Day 30, intramuscularly in the dominant arm. | Biological: GSK Biologicals' Candidate Tuberculosis Vaccine (692342) - Formulation 4 - Dosage 2<br>* Intramuscular injection, 2 doses<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Solicited Local Symptoms | Assessed solicited local symptoms included pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade. Grade 3 pain = pain that prevented normal activity. Grade 3 redness/swelling = redness/swelling spreading beyond 50 millimeters (mm) of injection site. Relationship analysis was not performed. | During the 7-day (Days 0-6) post-vaccination period, following each dose and across doses | 
| Number of Subjects With Solicited General Symptoms | Assessed solicited general symptoms included fatigue, temperature [defined as axillary temperature equal to or above 37.5 degrees Celsius (°C)], gastrointestinal symptoms (gastro) [nausea, vomiting, diarrhoea and/or abdominal pain], headache, malaise and myalgia. Any = occurrence of the symptom regardless of intensity grade. Grade 3 symptom = symptom that prevented normal activity. Grade 3 fever = fever ≥ 39.0 °C. Related = symptom assessed by the investigator as related to the vaccination. | During the 7-day (Days 0-6) post-vaccination period, following each dose and across doses | 
| Number of Subjects With Unsolicited Adverse Events (AEs) | 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. Grade 3 AE = an AE which prevented normal, everyday activities. Related = AE assessed by the investigator as related to the vaccination. | During the 30-day (Days 0-29) post-vaccination period | 
| Number of Subjects With Serious Adverse Events (SAEs) | 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. | During the entire study period (from Day 0 up to Day 210) | 
| Number of Subjects With Different Biochemical and Haematological Levels | Among biochemical and haematological parameters assessed were alanine aminotransferase [ALT], aspartate aminotransferase [AST], basophils [BAS], creatinine [CREA], eosinophils [EOS], haematocrit [Hct], haemoglobin [Hgb], lymphocytes [LYM], monocytes [MON], neutrophils [NEU], platelets [PLA], red blood cells [RBC] and white blood cells [WBC]. Levels of haematological/biochemical parameters assessed in terms of normal laboratory values were- normal, below and above. | At Day 0 | 
| Number of Subjects With Different Biochemical and Haematological Levels | Among biochemical and haematological parameters assessed were alanine aminotransferase [ALT], aspartate aminotransferase [AST], basophils [BAS], creatinine [CREA], eosinophils [EOS], haematocrit [Hct], haemoglobin [Hgb], lymphocytes [LYM], monocytes [MON], neutrophils [NEU], platelets [PLA], red blood cells [RBC] and white blood cells [WBC]. Levels of haematological/biochemical parameters assessed in terms of normal laboratory values were- normal, below and above. | At Day 7 | 
| Number of Subjects With Different Biochemical and Haematological Levels | Among biochemical and haematological parameters assessed were alanine aminotransferase [ALT], aspartate aminotransferase [AST], basophils [BAS], creatinine [CREA], eosinophils [EOS], haematocrit [Hct], haemoglobin [Hgb], lymphocytes [LYM], monocytes [MON], neutrophils [NEU], platelets [PLA], red blood cells [RBC] and white blood cells [WBC]. Levels of haematological/biochemical parameters assessed in terms of normal laboratory values were- normal, below and above. | At Day 30 | 
| Number of Subjects With Different Biochemical and Haematological Levels | Among biochemical and haematological parameters assessed were alanine aminotransferase [ALT], aspartate aminotransferase [AST], basophils [BAS], creatinine [CREA], eosinophils [EOS], haematocrit [Hct], haemoglobin [Hgb], lymphocytes [LYM], monocytes [MON], neutrophils [NEU], platelets [PLA], red blood cells [RBC] and white blood cells [WBC]. Levels of haematological/biochemical parameters assessed in terms of normal laboratory values were- normal, below and above. | At Day 37 | 
| Number of Subjects With Different Biochemical and Haematological Levels | Among biochemical and haematological parameters assessed were alanine aminotransferase [ALT], aspartate aminotransferase [AST], basophils [BAS], creatinine [CREA], eosinophils [EOS], haematocrit [Hct], haemoglobin [Hgb], lymphocytes [LYM], monocytes [MON], neutrophils [NEU], platelets [PLA], red blood cells [RBC] and white blood cells [WBC]. Levels of haematological/biochemical parameters assessed in terms of normal laboratory values were- normal, below and above. | At Day 60 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Mycobacterium Tuberculosis Fusion Protein (M72) Specific Cluster of Differentiation 4/8 (CD4/8+) T Cells Expressing at Least Two Different Cytokines | Among cytokines expressed were interleukin-2 [IL-2] and/or interferon-gamma [IFN-γ] and/or tumour necrosis factor-alpha [TNF-α] and/or cluster of differentiation 40-ligand [CD40-L]. Analysis of cytokines expression was done by means of in vitro flow cytometry, using intracellular cytokine staining (ICS). | At Day 0, 30, 60 and 210 | 
| Frequency of M72 Specific CD4/8+ T Cells Expressing at Least One Cytokine and Another Signal Molecule | Expressed cytokine combinations for CD4+ T cells were CD40-L and IL-2 or IFN-γ or TNF-α; IL-2 and CD40-L, or IFN-γ, or TNF-α; IFN-γ and CD40-L, or IL-2, or TNF-α; TNF-α and CD40-L, or IL-2, or IFN-γ. For CD8+ T cells no vaccine induced responses were observed, thus results are presented only for the frequency of M72-specific CD8+ T cells expressing at least two cytokines. | At Day 0, 30, 60 and 210 | 
| Anti-M72 Specific Antibody Concentrations | Concentrations given in enzyme-linked immunosorbent assay units per milliliter (EL.U/mL) were expressed as geometric mean concentrations (GMCs). | At Day 0, 30, 60 and 210 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tuberculosis vaccine