Safety and Immunogenicity Study of a Candidate Tuberculosis Vaccine in Human Immunodeficiency Virus (HIV)-Positive Adults

Study Overview
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Brief Summary
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The purpose of the study is to assess the safety and immunogenicity of a GlaxoSmithKline (GSK) Biologicals' candidate tuberculosis vaccine (692342) administered to Human Immunodeficiency Virus (HIV)-positive adults aged 18 to 59 years, living in a tuberculosis endemic region. Subjects will be followed-up for 3 years. Subjects will be enrolled in 3 cohorts: HIV-positive adults on highly active antiretroviral therapy HIV-positive adults not on highly active antiretroviral therapy HIV-negative adults Each cohort will have 2 groups.

Detailed Description
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This Protocol Posting has been updated following Protocol Amendment 1, February 2011, leading to the update of the outcome measures and the inclusion and exclusion criteria.

Official Title
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Safety and Immunogenicity of GSK Biologicals' Candidate Tuberculosis Vaccine (692342) When Administered to HIV-positive Adults Living in a Tuberculosis Endemic Region

Conditions
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Tuberculosis

Intervention / Treatment
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* Biological: GSK's investigational vaccine 692342
* Biological: Physiological saline


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. 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 prior to any study procedure. 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, 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. Clinically acceptable laboratory values at screening as determined by the investigator. No evidence of tuberculosis disease with no evidence of pulmonary pathology as confirmed by chest X-ray. No history of extra pulmonary tuberculosis. Based on their medical history, all subjects must have no history of chemotherapy for tuberculosis. Additional inclusion criteria for subjects to be enrolled in HIV+ on highly active antiretroviral therapy cohort: Subjects must be HIV-positive and under care of a physician for at least 6 months. Subjects must have a CD4+T cell count >= 250 cells/mm3 at screening. Subjects must be stable on highly active antiretroviral therapy for at least 6 months, with an undetectable HIV viral load level at screening. Additional inclusion criteria for subjects to be enrolled in HIV+ treatment naïve cohort: Subjects must be HIV-positive and under care of a physician for at least 6 months Subjects must be highly active antiretroviral therapy-naïve (never received anti-retroviral therapy after HIV diagnosis) Subjects must have a CD4 + T cell count above 350 cells/mm3 at screening. Subjects for whom commencement of highly active antiretroviral therapy is not expected based on current assessment within next year. Subjects must have a viral load between 5000 - 80000 copies/mL at screening. Additional inclusion criteria for subjects to be enrolled in HIV-negative cohort • Subjects must be negative for HIV-1. 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. History of previous administration of experimental Mtb vaccines. History of previous exposure to components of the investigational vaccine within 30 days preceding the first dose of study vaccine Chronic administration of immunosuppressant or other immune-modifying drugs within six months prior to the first vaccine/product dose. For corticosteroids, this will mean prednisone >= 20 mg/kg/day, or equivalent. Inhaled and topical steroids are allowed. Any condition or illness or medication, which in the opinion of the Investigator might interfere with the evaluation of the safety or immunogenicity of the vaccine. Planned participation or participation in another experimental protocol with an experimental product during the study period. Administration of any immunoglobulin, 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. Subjects taking any of the following medication: chronic administration of systemic steroids, interleukins, systemic interferon or systemic chemotherapy. History of allergic reactions or anaphylaxis to any drug or vaccine. 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 which in the Investigator's opinion would put the subject at risk. Pregnant female, lactating female or female planning to become pregnant or stop contraception. Acute or chronic clinically relevant pulmonary, cardiovascular, hepatic or renal function abnormality as determined by physical examination or laboratory screening tests. Additional exclusion criteria for subjects to be enrolled in HIV+ on highly active antiretroviral therapy cohort: Any change in anti-retroviral drug regimen within 12 weeks prior to screening. Any chronic drug therapy, other than highly active antiretroviral therapy or prophylaxis for opportunistic HIV related infections, birth control pills, anti-histamines for seasonal allergies and SSRIs.

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HIV(+)-HA/GSK692342<br>HIV-infected subjects between and including 18 to 59 years of age, who were on Highly Active Anti-Retroviral Therapy (HAART) at the time of study enrolment, received two doses of GSK692342 vaccine (TB) at Day 0 and Day 30, intramuscularly into the arm's deltoid region. | Biological: GSK's investigational vaccine 692342<br>* Intramuscular, 2 doses<br>|
| Placebo Comparator: HIV(+)-HA/Placebo<br>HIV-infected subjects between and including 18 to 59 years of age, who were on Highly Active Anti-Retroviral Therapy (HAART) at the time of study enrolment, received two doses of saline solution at Day 0 and Day 30, intramuscularly into the arm's deltoid region. | Biological: Physiological saline<br>* Intramuscular, 2 doses<br>|
| Experimental: HIV(+)-TN/GSK692342<br>HIV-infected subjects between and including 18 to 59 years of age, who were HAART-treatment naive (TN) at the time of study enrolment, received two doses of GSK692342 vaccine (TB) at Day 0 and Day 30, intramuscularly into the arm's deltoid region. | Biological: GSK's investigational vaccine 692342<br>* Intramuscular, 2 doses<br>|
| Placebo Comparator: HIV(+)-TN/Placebo<br>HIV-infected subjects between and including 18 to 59 years of age, who were HAART-treatment naive (TN) at the time of study enrolment, received two doses of saline solution at Day 0 and Day 30, intramuscularly into the arm's deltoid region. | Biological: Physiological saline<br>* Intramuscular, 2 doses<br>|
| Experimental: HIV(-)/GSK692342<br>Subjects between and including 18 to 59 years of age, who were HIV-negative at the time of study enrolment, received two doses of GSK692342 vaccine (TB) at Day 0 and Day 30, intramuscularly into the arm's deltoid region. | Biological: GSK's investigational vaccine 692342<br>* Intramuscular, 2 doses<br>|
| Placebo Comparator: HIV(-)/Placebo<br>Subjects between and including 18 to 59 years of age, who were HIV-negative at the time of study enrolment, received two doses of saline solution at Day 0 and Day 30, intramuscularly into the arm's deltoid region. | Biological: Physiological saline<br>* Intramuscular, 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 Grade 3 Solicited Local Symptoms | Solicited local symptoms assessed were pain and swelling. Grade 3 pain = pain that prevented normal activity. Grade 3 swelling = swelling spreading beyond 50 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 Grade 3 Solicited General Symptoms | Solicited general symptoms assessed were 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. Grade 3 symptom = symptom that prevented normal activity. Grade 3 fever = fever ≥ 39.5 °C. | During the 7-day (Days 0-6) post-vaccination period following each dose and across doses | 
| Number of Subjects With Grade 3 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 out-side the specified period of follow-up for solicited symptoms. Grade 3 AE = an AE which prevented normal, everyday activities. | 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. | From screening up to one month post Dose 2 | 
| Number of Subjects With Grade 3 and Grade 4 Haematological and Biochemical Levels | Haematological and biochemical parameters assessed were haemoglobin [Hgb], white blood cells [WBC], platelets [PLA], alanine aminotransferase [ALT], aspartate aminotransferase [AST] and creatinine [CREA]. The haematology and biochemistry toxicity grading scale was based on the Guidance for Industry - Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. | At Day 0 | 
| Number of Subjects With Grade 3 and 4 Haematological and Biochemical Levels | Haematological and biochemical parameters assessed were haemoglobin [Hgb], white blood cells [WBC], platelets [PLA], alanine aminotransferase [ALT], aspartate aminotransferase [AST] and creatinine [CREA]. The haematology and biochemistry toxicity grading scale was based on the Guidance for Industry - Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. | At Day 7 | 
| Number of Subjects With Grade 3 and Grade 4 Haematological/Biochemical Levels | Haematological and biochemical parameters assessed were haemoglobin [Hgb], white blood cells [WBC], platelets [PLA], alanine aminotransferase [ALT], aspartate aminotransferase [AST] and creatinine [CREA]. The haematology and biochemistry toxicity grading scale was based on the Guidance for Industry - Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. | At Day 30 | 
| Number of Subjects With Grade 3-4 Haematological and Biochemical Levels | Haematological and biochemical parameters assessed were haemoglobin [Hgb], white blood cells [WBC], platelets [PLA], alanine aminotransferase [ALT], aspartate aminotransferase [AST] and creatinine [CREA]. The haematology and biochemistry toxicity grading scale was based on the Guidance for Industry - Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. | At Day 37 | 
| Number of Subjects With Grade 3-4 Haematological/Biochemical Levels | Haematological and biochemical parameters assessed were haemoglobin [Hgb], white blood cells [WBC], platelets [PLA], alanine aminotransferase [ALT], aspartate aminotransferase [AST] and creatinine [CREA]. The haematology and biochemistry toxicity grading scale was based on the Guidance for Industry - Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. | At Day 60 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-Mycobacterium Tuberculosis Fusion Protein (M72) Specific Antibody Concentrations | Concentration of M72-specific antibodies, as measured by the enzyme-linked immunosorbent assay (ELISA), were given in ELISA units per milliliter (EU/mL) and expressed as geometric mean concentrations (GMCs). | At Days 0, 30, 60, 210 and at Years 1, 2 and 3 | 
| Number of Seroconverted Subjects for M72-specific Antibodies | A seroconverted subject for M72 antibodies was defined as a seronegative subject at baseline, with the appearance of M72 antibody concentration higher than or equal to (≥) the cut-off value of 2.8 EL.U/mL post vaccination. Antibody concentrations below the cut-off value of the assay were given an arbitrary value of half the cut-off value for the purpose of GMC calculation. | At Days 0, 30, 60, 210 and at Years 1, 2 and 3 | 
| Frequency of M72-cluster of Differentiation 4 (CD4+) T-cells Expressing at Least 2 Immune Markers | Among immune markers expressed after background reduction were interleukin-2 (IL-2), interferon-gamma (IFN-γ), tumour necrosis factor-alpha (TNF-α) and cluster of differentiation 40 - ligand (CD40-L). This endpoint presents results for CD4-all doubles. | At Days 0, 7, 30, 37, 60, 210 and at Years 1, 2 and 3 | 
| Frequency of M72-CD4+ T-cells Expressing Any Combination of Cytokines | Among cytokines expressed after background reduction were cluster of differentiation 40-ligand (CD40-L), interleukin-2 (IL-2), interferon-gamma (IFN-γ) and tumour necrosis factor-alpha (TNF-α). This endpoint presents results for the following cytokine combinations: CD4.CD40L(+)+IL2(+)+TNFa(+)+IFNg(+), CD4.CD40L(+)+IL2(+)+TNFa(+)+IFNg(-),CD4.CD40L(+)+IL2(+)+TNFa(-)+IFNg(+),CD4.CD40L(+)+IL2(+)+TNFa(-)+IFNg(-),CD4.CD40L(+)+IL2(-)+TNFa(+)+IFNg(+). | At Days 0, 7, 30, 37, 60, 210 and at Years 1, 2 and 3 | 
| M72-cluster of Differentiation 4 (CD4+) T-cells Frequency Expressing Any Combination of Cytokines | Among cytokines expressed after background reduction were cluster of differentiation 40-ligand (CD40-L), interleukin-2 (IL-2), interferon-gamma (IFN-γ) and tumour necrosis factor-alpha (TNF-α). This endpoint presents results for the following cytokine combination: CD4.CD40L(+)+IL2(-)+TNFa(+)+IFNg(-), CD4.CD40L(+)+IL2(-)+TNFa(-)+IFNg(+),CD4.CD40L(+)+IL2(-)+TNFa(-)+IFNg(-),CD4.CD40L(-)+IL2(+)+TNFa(+)+IFNg(+),CD4.CD40L(-)+IL2(+)+TNFa(+)+IFNg(-) | At Days 0, 7, 30, 37, 60, 210 and at Years 1, 2 and 3 | 
| M72-CD4+ T-cells Frequency Expressing Any Combination of Cytokines | Among cytokines expressed after background reduction were cluster of differentiation 40-ligand (CD40-L), interleukin-2 (IL-2), interferon-gamma (IFN-γ) and tumour necrosis factor-alpha (TNF-α). This endpoint presents results for the following cytokine combination: CD4.CD40L(-)+IL2(+)+TNFa(-)+IFNg(+), CD4.CD40L(-)+IL2(+)+TNFa(-)+IFNg(-),CD4.CD40L(-)+IL2(-)+TNFa(+)+IFNg(+),CD4.CD40L(-)+IL2(-)+TNFa(+)+IFNg(-), CD4.CD40L(-)+IL2(-)+TNFa(-)+IFNg(+). | At Days 0, 7, 30, 37, 60, 210 and at Years 1, 2 and 3 | 
| Frequency of M72-cluster of Differentiation 8 (CD8+) T-cells Expressing at Least 2 Immune Markers | Among immune markers expressed after background reduction were interleukin-2 (IL-2), interferon-gamma (IFN-γ) and tumour necrosis factor-alpha (TNF-α). This endpoint presents results for CD8-all doubles. | At Days 0, 7, 30, 37, 60, 210 and at Years 1, 2 and 3 | 
| Frequency of M72-CD8+ T-cells Expressing Any Combination of Cytokines | Among cytokines expressed after background reduction were cluster of differentiation 40-ligand (CD40-L) interleukin-2 (IL-2), interferon-gamma (IFN-γ) and tumour necrosis factor-alpha (TNF-α). This endpoint presents results for the following cytokine combination: CD8.CD40L(+)+IL2(+)+TNFa(+)+IFNg(+),CD8.CD40L(+)+IL2(+)+TNFa(+)+IFNg(-),CD8.CD40L(+)+IL2(+)+TNFa(-)+IFNg(+),CD8.CD40L(+)+IL2(+)+TNFa(-)+IFNg(-),CD8.CD40L(+)+IL2(-)+TNFa(+)+IFNg(+). | At Days 0, 7, 30, 37, 60, 210 and at Years 1, 2 and 3 | 
| M72-cluster of Differentiation 8 (CD8+) T Frequency Cells Expressing Any Combination of Cytokines | Among cytokines expressed after background reduction were cluster of differentiation 40-ligand (CD40-L) interleukin-2 (IL-2), interferon-gamma (IFN-γ) and tumour necrosis factor-alpha (TNF-α). This endpoint presents results for the following cytokine combination: CD8.CD40L(+)+IL2(-)+TNFa(+)+IFNg(-),CD8.CD40L(+)+IL2(-)+TNFa(-)+IFNg(+),CD8.CD40L(+)+IL2(-)+TNFa(-)+IFNg(-),CD8.CD40L(-)+IL2(+)+TNFa(+)+IFNg(+),CD8.CD40L(-)+IL2(+)+TNFa(+)+IFNg(-). | At Days 0, 7, 30, 37, 60, 210 and at Years 1, 2 and 3 | 
| M72-CD8+ T-cells Frequency Expressing Any Combination of Cytokines | Among cytokines expressed after background reduction were cluster of differentiation 40-ligand (CD40-L) interleukin-2 (IL-2), interferon-gamma (IFN-γ) and tumour necrosis factor-alpha (TNF-α). This endpoint presents results for the following cytokine combination: CD8.CD40L(-)+IL2(+)+TNFa(-)+IFNg(+), CD8.CD40L(-)+IL2(+)+TNFa(-)+IFNg(-),CD8.CD40L(-)+IL2(-)+TNFa(+)+IFNg(+), CD8.CD40L(-)+IL2(-)+TNFa(+)+IFNg(-),CD8.CD40L(-)+IL2(-)+TNFa(-)+IFNg(+). | At Days 0, 7, 30, 37, 60, 210 and at Years 1, 2 and 3 | 
| Number of Subjects With Any Solicited Local Symptoms | Solicited local symptoms assessed were pain and swelling. Any = occurrence of the symptom regardless of intensity grade. | During the 7-day (Days 0-6) post-vaccination period following each dose and across doses | 
| Number of Subjects With Any Solicited General Symptoms | Solicited general symptoms assessed were fatigue, gastrointestinal symptoms (Gastro), headache, malaise, myalgia and temperature. Any = occurrence of the symptom regardless of intensity grade. | During the 7-day (Days 0-6) post-vaccination period following each dose and across doses | 
| Number of Subjects With Any Unsolicited 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. | During the 30-day (Days 0-29) post-vaccination period | 
| Number of Subjects With 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. | From one month post Dose 2 up to study end (Year 3) | 
| Number of Subjects Presenting Different Grades of Haematological and Biochemical Values | Biochemical and haematological parameters included haemoglobin [Hgb], white blood cells [WBC], platelets [PLA], alanine aminotransferase [ALT], aspartate aminotransferase [AST] and creatinine [CREA]. Levels assessed were - normal, grade 1, grade 2 and missing grade. The haematology and biochemistry toxicity grading scale was based on the Guidance for Industry - Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. | At Days 0, 7, 30, 37 and 60 | 

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