Safety and Immunogenicity of a Candidate Tuberculosis (TB) Vaccine in Adults With TB Disease

Study Overview
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Brief Summary
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This study will assess the safety and immunogenicity of GSK Biologicals' investigational tuberculosis (TB) vaccine (GSK 692342) compared to placebo when administered at 0, 1 months to human immunodeficiency virus (HIV) negative adults who have received treatment for TB disease (denoted TB-treated cohort) or are currently receiving treatment for TB disease (denoted TB-treatment cohort). For comparative purposes, subjects who have never had TB disease (denoted TB-naïve cohort) will also be enrolled.

Detailed Description
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A Protocol Amendment 1, May 2012, was made following the decision to add a second country in the study (i.e. Estonia).

Official Title
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Safety and Immunogenicity Study of GSK Biologicals' Candidate Tuberculosis (TB) Vaccine GSK 692342 When Administered to Adults With TB Disease

Conditions
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Tuberculosis

Intervention / Treatment
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* Biological: GSK Biologicals' investigational TB vaccine GSK 692342
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who the investigator believes can and will comply with the requirements of the protocol. A male or female between, and including, 18 and 59 years of age at the time of the first vaccination. Written informed consent obtained from the subject. 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 vaccination, and has agreed to continue adequate contraception during the entire treatment period and for 2 months after completion of the vaccination series. Seronegative for HIV- 1 and -2 antibodies. No history of or current extrapulmonary tuberculosis TB. Additionally, based on medical history, Subjects in the TB-naive cohort must have no active pulmonary disease as indicated by chest X-ray. have no signs and symptoms of TB. have no history of chemoprophylaxis or treatment for TB. Subjects in the TB-treated cohort must have a history of successful treatment for pulmonary TB (completed at least 1 year prior to vaccination). have no active pulmonary disease on chest X-ray. Subjects in the TB-treatment cohort must - have documented treatment for pulmonary TB (smear- or culture confirmed) ongoing for 2-4 months prior to vaccination. Exclusion Criteria: Use of any investigational or non-registered product other than the study vaccine within 30 days preceding the first dose of study vaccine, or planned use during the study period. Administration of a registered live vaccine not foreseen by the study within 30 days preceding the first dose of study vaccine and administration of a registered inactivated vaccine within 14 days preceding the first dose of study vaccine. 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, which in the opinion of the investigator could adversely interfere with the vaccine. History of previous administration of experimental TB vaccines. History of previous exposure to components of the investigational vaccine within 30 days preceding the first dose of study vaccine. Administration of any immunoglobulins, any immunotherapy and/or any blood products within the 3 months preceding the first dose of study vaccination, or planned administrations during the study period. Planned participation or participation in another experimental protocol during the study period. Any confirmed or suspected immunosuppressive or immunodeficient condition based on medical history and physical examination. History of chronic alcohol and/or drug abuse. History of allergic disease or reactions likely to be exacerbated by any component of the vaccine. Major congenital defects. Pregnant female, lactating female or female planning to become pregnant or discontinue contraceptive precautions during the active phase of the study (from study start till 2 months after dose 2). Additionally, for the TB naïve and TB treated cohorts: - Acute or chronic clinically relevant pulmonary, cardiovascular, hepatic or renal function abnormality as determined by physical examination or laboratory screening tests Additionally, for the TB treatment cohort: Acute or chronic clinically relevant pulmonary, cardiovascular, hepatic or renal function abnormality as determined by physical examination or laboratory screening tests. Individuals with grade 3 levels will be excluded. Failure to convert while on anti-TB treatment at the end of the second month of anti-TB therapy.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 59 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 |
| --- | --- |
| Experimental: Group A<br>Subjects from TB-treated cohort will receive 2 doses of GSK's investigational vaccine GSK 692342. | Biological: GSK Biologicals' investigational TB vaccine GSK 692342<br>* Intramuscular injection, 2 doses<br>|
| Placebo Comparator: Group B<br>Subjects from TB-treated cohort will receive 2 doses of physiological Saline. | Biological: Placebo<br>* Intramuscular injection, 2 doses<br>|
| Experimental: Group C<br>Subjects from TB-treatment cohort will receive 2 doses of GSK's investigational vaccine GSK 692342. | Biological: GSK Biologicals' investigational TB vaccine GSK 692342<br>* Intramuscular injection, 2 doses<br>|
| Placebo Comparator: Group D<br>Subjects from TB-treatment cohort will receive 2 doses of physiological Saline. | Biological: Placebo<br>* Intramuscular injection, 2 doses<br>|
| Experimental: Group E<br>Subjects from TB-naive cohort will receive 2 doses of GSK's investigational vaccine GSK 692342. | Biological: GSK Biologicals' investigational TB vaccine GSK 692342<br>* Intramuscular injection, 2 doses<br>|
| Placebo Comparator: Group F<br>Subjects from TB-naive cohort will receive 2 doses of physiological Saline. | Biological: Placebo<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 Any and Grade 3 Solicited Local Symptoms | 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. Grade 3 redness/swelling = redness/swelling spreading beyond (>) 100 millimeters (mm) of injection site. | During the 7-day (Days 0-6) post-vaccination period following each dose and across doses | 
| Number of Subjects With Any, Grade 3 and Related Solicited General Symptoms | Assessed solicited general symptoms were fatigue, gastrointestinal symptoms, headache, malaise, myalgia and temperature [body temperature equal to or above (≥) 37.5 degrees Celsius (°C)]. Any = occurrence of any solicited general symptom regardless of their intensity grade or relationship to vaccination. Grade 3 symptom = symptom that prevented normal activity. Grade 3 temperature = body temperature above (>) 39.5°C. Related = event assessed by the investigator as causally related to the study vaccination. | During the 7-day (Days 0-6) post-vaccination period following each dose and across doses | 
| Number of Subjects With 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. | During the 30 day (Days 0-29), after vaccination | 
| 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. | Up to day 210 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Anti-Mycobacterium Tuberculosis Fusion Protein M72 Antibodies | Cut-off values assessed were greater than or equal to (≥) 2.8, as measured by Enzyme-Linked Immunosorbent Assay (ELISA) in the sera of subjects seronegative before vaccination. | Prior to dose 1 (Day 0), post-dose 1 (Day 30), post-dose 2 (Days 60 and 210) | 
| Concentrations of Anti-M72 Antibodies | Concentrations are presented as geometric mean concentrations (GMCs) and expressed in ELISA units per milliliter (EU/mL). | Prior to dose 1 (Day 0), post-dose 1 (Day 30), post-dose 2 (Days 60 and 210) | 
| Frequency of M72-specific Cluster of Differentiation 4 (CD4+) T-cells Expressing Any Combination of the Different Immune Markers | Immune markers expressed were among Interleukin-2 (IL-2), Interferon-gamma (IFN-g), Tumour necrosis factor-alpha (TNF-a) and/or CD40-ligand (CD40-L). | Prior to dose 1 (Day 0), post-dose 1 (Days 7 and 30), post-dose 2 (Days 37, 60 and 210) | 
| Frequency of M72-specific CD4+ T-cells Expressing at Least 2 Immune Markers Among 6 | Immune markers expressed were among Interleukin-2 (IL-2), Interferon-gamma (IFN-g), Tumour necrosis factor-alpha (TNF-a), CD40-ligand (CD40-L), Interleukin-17 (IL-17) and/or Interleukin-13 (IL-13). | Prior to dose 1 (Day 0), post-dose 1 (Days 7 and 30), post-dose 2 (Days 37, 60 and 210) | 
| Frequency of M72-specific CD4+ T-cells Expressing Any Combination of Cytokines | Immune markers (cytokines) expressed were among Interleukin-2 (IL-2), Interferon-gamma (IFN-g), Tumour necrosis factor-alpha (TNF-a) and/or CD40-ligand (CD40-L). | Prior to dose 1 (Day 0), post-dose 1 (Days 7 and 30), post-dose 2 (Days 37, 60 and 210) | 
| Frequency of M72-specific CD4+ T-cells Expressing Any Combination of Immune Markers | Immune markers expressed were among Interleukin-2 (IL-2), Interferon-gamma (IFN-g), Tumour necrosis factor-alpha (TNF-a) and/or CD40-ligand (CD40-L). | Prior to dose 1 (Day 0), post-dose 1 (Days 7 and 30), post-dose 2 (Days 37, 60 and 210) | 
| Frequency of CD4+ T-cells M72-specific Expressing Any Combination of Cytokines | Immune markers (cytokines) expressed were among Interleukin-2 (IL-2), Interferon-gamma (IFN-g), Tumour necrosis factor-alpha (TNF-a) and/or CD40-ligand (CD40-L). | Prior to dose 1 (Day 0), post-dose 1 (Days 7 and 30), post-dose 2 (Days 37, 60 and 210) | 
| Frequency of CD4+ T-cells M72-specific Expressing Any Combination of Immune Markers | Immune markers expressed were among Interleukin-2 (IL-2), Interferon-gamma (IFN-g), Tumour necrosis factor-alpha (TNF-a) and/or CD40-ligand (CD40-L). | Prior to dose 1 (Day 0), post-dose 1 (Days 7 and 30), post-dose 2 (Days 37, 60 and 210) | 
| Frequency of M72-specific CD4+ T-cells Expressing Cytokines in Any Combination | Immune markers (cytokines) expressed were among Interleukin-2 (IL-2), Interferon-gamma (IFN-g), Tumour necrosis factor-alpha (TNF-a) and/or CD40-ligand (CD40-L). | Prior to dose 1 (Day 0), post-dose 1 (Days 7 and 30), post-dose 2 (Days 37, 60 and 210) | 
| Frequency of M72-specific CD4+ T-cells Expressing Immune Markers in Any Combination | Immune markers expressed were among Interleukin-2 (IL-2), Interferon-gamma (IFN-g), Tumour necrosis factor-alpha (TNF-a) and/or CD40-ligand (CD40-L). | Prior to dose 1 (Day 0), post-dose 1 (Days 7 and 30), post-dose 2 (Days 37, 60 and 210) | 
| Frequency of CD4+ T-cells M72-specific Expressing Cytokines in Any Combination | Immune markers (cytokines) expressed were among Interleukin-2 (IL-2), Interferon-gamma (IFN-g), Tumour necrosis factor-alpha (TNF-a) and/or CD40-ligand (CD40-L). | Prior to dose 1 (Day 0), post-dose 1 (Days 7 and 30), post-dose 2 (Days 37, 60 and 210) | 
| Frequency of CD4+ T-cells M72-specific Expressing Immune Markers in Any Combination | Immune markers expressed were among Interleukin-2 (IL-2), Interferon-gamma (IFN-g), Tumour necrosis factor-alpha (TNF-a) and/or CD40-ligand (CD40-L). | Prior to dose 1 (Day 0), post-dose 1 (Days 7 and 30), post-dose 2 (Days 37, 60 and 210) | 
| Frequency of M72-specific Cluster of Differentiation 8 (CD8+) T-cells Expressing at Least 2 Immune Markers | Immune markers expressed were among Interleukin-2 (IL-2), Interferon-gamma (IFN-g), Tumour necrosis factor-alpha (TNF-a) and/or CD40-ligand (CD40-L). | Prior to dose 1 (Day 0), post-dose 1 (Days 7 and 30), post-dose 2 (Days 37, 60 and 210) | 
| Frequency of M72-specific CD8+ T-cells Expressing at Least 2 Immune Markers Among 6 | Immune markers expressed were among Interleukin-2 (IL-2), Interferon-gamma (IFN-g), Tumour necrosis factor-alpha (TNF-a), CD40-ligand (CD40-L), Interleukin-17 (IL-17) and/or Interleukin-13 (IL-13). | Prior to dose 1 (Day 0), post-dose 1 (Days 7 and 30), post-dose 2 (Days 37, 60 and 210) | 
| Frequency of M72-specific CD8+ T-cells Expressing Any Combination of Immune Markers | Immune markers expressed were among Interleukin-2 (IL-2), Interferon-gamma (IFN-g), Tumour necrosis factor-alpha (TNF-a) and/or CD40-ligand (CD40-L). | Prior to dose 1 (Day 0), post-dose 1 (Days 7 and 30), post-dose 2 (Days 37, 60 and 210) | 
| Frequency of M72-specific CD8+ T-cells Expressing Any Combination of Cytokines | Immune markers (cytokines) expressed were among Interleukin-2 (IL-2), Interferon-gamma (IFN-g), Tumour necrosis factor-alpha (TNF-a) and/or CD40-ligand (CD40-L). | Prior to dose 1 (Day 0), post-dose 1 (Days 7 and 30), post-dose 2 (Days 37, 60 and 210) | 
| Frequency of CD8+ T-cells M72-specific Expressing Any Combination of Immune Markers | Immune markers expressed were among Interleukin-2 (IL-2), Interferon-gamma (IFN-g), Tumour necrosis factor-alpha (TNF-a) and/or CD40-ligand (CD40-L). | Prior to dose 1 (Day 0), post-dose 1 (Days 7 and 30), post-dose 2 (Days 37, 60 and 210) | 
| Frequency of CD8+ T-cells M72-specific Expressing Any Combination of Cytokines | Immune markers (cytokines) expressed were among Interleukin-2 (IL-2), Interferon-gamma (IFN-g), Tumour necrosis factor-alpha (TNF-a) and/or CD40-ligand (CD40-L). | Prior to dose 1 (Day 0), post-dose 1 (Days 7 and 30), post-dose 2 (Days 37, 60 and 210) | 
| Frequency of M72-specific CD8+ T-cells Expressing Cytokines in Any Combination | Immune markers (cytokines) expressed were among Interleukin-2 (IL-2), Interferon-gamma (IFN-g), Tumour necrosis factor-alpha (TNF-a) and/or CD40-ligand (CD40-L). | Prior to dose 1 (Day 0), post-dose 1 (Days 7 and 30), post-dose 2 (Days 37, 60 and 210) | 
| Frequency of M72-specific CD8+ T-cells Expressing Immune Markers in Any Combination | Immune markers expressed were among Interleukin-2 (IL-2), Interferon-gamma (IFN-g), Tumour necrosis factor-alpha (TNF-a) and/or CD40-ligand (CD40-L). | Prior to dose 1 (Day 0), post-dose 1 (Days 7 and 30), post-dose 2 (Days 37, 60 and 210) | 
| Frequency of CD8+ T-cells M72-specific Expressing Cytokines in Any Combination | Immune markers (cytokines) expressed were among Interleukin-2 (IL-2), Interferon-gamma (IFN-g), Tumour necrosis factor-alpha (TNF-a) and/or CD40-ligand (CD40-L). | Prior to dose 1 (Day 0), post-dose 1 (Days 7 and 30), post-dose 2 (Days 37, 60 and 210) | 
| Frequency of CD8+ T-cells M72-specific Expressing Immune Markers in Any Combination | Immune markers expressed were among Interleukin-2 (IL-2), Interferon-gamma (IFN-g), Tumour necrosis factor-alpha (TNF-a) and/or CD40-ligand (CD40-L). | Prior to dose 1 (Day 0), post-dose 1 (Days 7 and 30), post-dose 2 (Days 37, 60 and 210) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tuberculosis vaccine, HIV-negative, tuberculosis treatment