Study to Evaluate GSK Biologicals' Herpes Zoster Vaccine GSK1437173A in Human Immunodeficiency Virus (HIV)-Infected Subjects

Study Overview
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Brief Summary
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This observer-blind study will evaluate the safety and immunogenicity of GlaxoSmithKline (GSK) Biologicals' investigational Herpes Zoster (HZ) vaccine GSK1437173A in Human Immunodeficiency Virus (HIV) infected subjects, firstly enrolling subjects treated with antiretroviral therapy (ART) and with high CD4 T cell counts, and subsequently ART-treated subjects with low CD4 T cell counts, and ART-naïve subjects with high CD4 T cell counts. This Protocol Posting has been updated following Amendment 1 of the Protocol, August 2010. The impacted sections is exclusion criteria.

Official Title
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Safety and Immunogenicity of GlaxoSmithKline Biologicals' Herpes Zoster Vaccine 1437173A in Adult HIV-infected Subjects

Conditions
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Herpes Zoster

Intervention / Treatment
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* Biological: Herpes Zoster Vaccine GSK1437173A
* Biological: Placebo


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; Male and female subjects at least 18 years old at the time of vaccination; Subjects born before 1985 and not from a tropical region. Subjects born in 1985 or later and subjects born before 1985 in tropical regions must have a history of Varicella Zoster virus (VZV) infection or serological evidence of prior VZV infection; Written informed consent obtained from the subject; Female subjects of non-childbearing potential may be enrolled in the study; Non-childbearing potential is defined as current tubal ligation, hysterectomy, ovariectomy or post-menopause. OR 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; Known to be human immunodeficiency virus-1 (HIV-1) infected, diagnosed at least 1 year prior to enrolment; For the antiretroviral therapyART High CD4 and ART Low CD4 cohorts: Stable on ART for at least one year CD4 T cell count >= 50 cells /mm3 at screening Undetectable VL at screening; For the non-ART High CD4 cohort: ART-naïve subjects who have never received anti-retroviral therapy after HIV diagnosis and for whom commencement of ART is not expected based on current assessment within next seven months; HIV VL >= 1000 copies/mL and <= 100 000 copies/mL at screening CD4 T cell count >= 500 cells/mm3 at screening. 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; Vaccination against varicella or herpes zoster (HZ) within the previous 12 months; Occurrence of a varicella or HZ episode within the previous 12 months; History of allergic disease or reactions likely to be exacerbated by any component of the vaccine. Additionally, consider allergic reactions to other material or equipment related to study participation. Please note, the vaccine and vials in this study do not contain latex; Has currently an Acquired Immunodeficiency Syndrome (AIDS) defining condition; Opportunistic infection or AIDS-associated malignancy in the previous year; Any confirmed or suspected immunosuppressive or immunodeficient condition resulting from disease other than HIV infection or immunosuppressive/cytotoxic therapy; Administration of immunoglobulins, and/or any blood products within 90 days preceding the first dose of study vaccine/placebo or planned administration during the study period; Chronic administration of immunosuppressive or other immune-modifying drugs within 6 months prior to the first vaccine dose; Administration and/or planned administration of a vaccine not foreseen by the study protocol within 30 days before dose 1, dose 2 and/or 3 of vaccine and/or within 30 days after any dose. However, licensed non-replicating vaccines may be administered up to 8 days prior to dose 1, 2 and/or 3, and/or at least 14 days after any dose of study vaccine; 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; Acute disease at the time of enrolment; Any contraindication to receiving intramuscular injections; Any condition or illness which might interfere with the evaluation of the safety or immunogenicity of the vaccine; Active hepatitis B (HBV) infection or active hepatitis C (HCV) infection. Current use of HIV fusion inhibitors, chemokine (C-C motif) receptor (CCR5) inhibitors or Interleukin-2/ Interleukin-7/ Interferon; For subjects in the ART cohorts, any change in anti-retroviral drug regimen within 12 weeks prior to vaccination; Pregnant or lactating female; Female planning to become pregnant or planning to discontinue contraceptive precautions; Abnormal biochemical and hematological laboratory values obtained for blood samples collected at screening.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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: GSK1437173A Group<br>Subjects who received three doses of GSK1437173A vaccine (Months 0, 2 and 6), administered intramuscularly, in the deltoid muscle of the non-dominant arm. | Biological: Herpes Zoster Vaccine GSK1437173A<br>* intramuscular injection<br>* Other names: HZ/su vaccine;|
| Placebo Comparator: Placebo Group<br>Subjects who received three doses of placebo (Months 0, 2 and 6), administered intramuscularly, in the deltoid muscle of the non-dominant arm. | Biological: Placebo<br>* intramuscular injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Month 0 to Month 18 | 
| Number of Subjects With SAEs Related to Study Participation or to a Concurrent GSK Medication/Vaccine | 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 21 days prior to Month 0) until Month 18 | 
| Number of Subjects With Any Fatal 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 21 days prior to Month 0) until Month 18 | 
| Number of Subjects With Any Adverse Events (AEs) of Specific Interest | AEs of specific interest include new onset of autoimmune diseases (NOADs) and other immune mediated inflammatory disorders from administration of the first dose of vaccine/placebo. | From Month 0 until Month 18 | 
| Number of Subjects With Any, Grade 3 and Related Solicited Local Symptoms | Assessed solicited local symptoms were pain, redness and swelling. Any = incidence of a particular symptom regardless of their intensity grade. Grade 3 pain = pain that prevented normal activity. Grade 3 redness/swelling = redness/swelling spreading beyond 100 millimeters (mm) of injection site. | Within 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 included nausea, vomiting, diarrhoea and/or abdominal pain), headache, myalgia, shivering and temperature [defined as oral/axillary temperature above (>) 37.5 degrees Celsius (°C)]. Any = incidence of a particular symptom regardless of their intensity grade or relationship to vaccination. 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. | Within the 7-day (Days 0-6) post-vaccination period following each dose and across doses | 
| Number of Subjects With 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. Grade 3 AE = an AE which prevented normal, everyday activities. Related = AE assessed by the investigator as related to the vaccination. | Within 30 days (Days 0-29) after each vaccination | 
| Number of Subjects With Any Hematological and Biochemical Parameters Below, Within or Above Normal Laboratory Ranges | The assessed parameters were Alanine Aminotransferase, Albumin, Alkaline Phosphatase, Aspartate Aminotransferase, Basophils, Bilirubin Total, Bilirubin Conjugated / Direct, Creatinine, Eosinophils, Glucose, Bicarbonate, Haemoglobin, Potassium, Lymphocytes, Monocytes, Sodium, Neutrophils, Platelets and White Blood Cells. Tabulation was made by relation to the normal laboratory ranges: below, within or above, and also status unknown. | At Screening Visit (up to 21 days prior to Month 0) | 
| Number of Subjects With Any Hematological and Biochemical Parameters Below, Within or Above Normal Laboratory Ranges | The assessed parameters were Alanine Aminotransferase, Albumin, Alkaline Phosphatase, Aspartate Aminotransferase, Basophils, Bilirubin Total, Bilirubin Conjugated / Direct, Creatinine, Eosinophils, Glucose, Bicarbonate, Haemoglobin, Potassium, Lymphocytes, Monocytes, Sodium, Neutrophils, Platelets and White Blood Cells. Tabulation was made by relation to the normal laboratory ranges: below, within or above, and also status unknown. | At Month 1 | 
| Number of Subjects With Any Hematological and Biochemical Parameters Below, Within or Above Normal Laboratory Ranges | The assessed parameters were Alanine Aminotransferase, Albumin, Alkaline Phosphatase, Aspartate Aminotransferase, Basophils, Bilirubin Total, Bilirubin Conjugated / Direct, Creatinine, Eosinophils, Glucose, Bicarbonate, Haemoglobin, Potassium, Lymphocytes, Monocytes, Sodium, Neutrophils, Platelets and White Blood Cells. Tabulation was made by relation to the normal laboratory ranges: below, within or above, and also status unknown. | At Month 2 | 
| Number of Subjects With Any Hematological and Biochemical Parameters Below, Within or Above Normal Laboratory Ranges | The assessed parameters were Alanine Aminotransferase, Albumin, Alkaline Phosphatase, Aspartate Aminotransferase, Basophils, Bilirubin Total, Bilirubin Conjugated / Direct, Creatinine, Eosinophils, Glucose, Bicarbonate, Haemoglobin, Potassium, Lymphocytes, Monocytes, Sodium, Neutrophils, Platelets and White Blood Cells. Tabulation was made by relation to the normal laboratory ranges: below, within or above, and also staus unknown. | At Month 3 | 
| Number of Subjects With Any Hematological and Biochemical Parameters Below, Within or Above Normal Laboratory Ranges | The assessed parameters were Alanine Aminotransferase, Albumin, Alkaline Phosphatase, Aspartate Aminotransferase, Basophils, Bilirubin Total, Bilirubin Conjugated / Direct, Creatinine, Eosinophils, Glucose, Bicarbonate, Haemoglobin, Potassium, Lymphocytes, Monocytes, Sodium, Neutrophils, Platelets and White Blood Cells. Tabulation was made by relation to the normal laboratory ranges: below, within or above, and also status unknown. | At Month 6 | 
| Number of Subjects With Any Hematological and Biochemical Parameters Below, Within or Above Normal Laboratory Ranges | The assessed parameters were Alanine Aminotransferase, Albumin, Alkaline Phosphatase, Aspartate Aminotransferase, Basophils, Bilirubin Total, Bilirubin Conjugated / Direct, Creatinine, Eosinophils, Glucose, Bicarbonate, Haemoglobin, Potassium, Lymphocytes, Monocytes, Sodium, Neutrophils, Platelets and White Blood Cells. Tabulation was made by relation to the normal laboratory ranges: below, within or above, and also staus unknown. | At Month 7 | 
| Number of Subjects With Any Significant Change in Antiretroviral Therapy (ART), Including Initiation of ART in ART-naïve Subjects | In this analysis, results were tabulated for the main study groups. Significant changes to ART appeared due to failure to control HIV viral load and due to failure to maintain high CD4 cells count. | From Month 0 until Month 18 | 
| Number of Subjects With Any AIDS-defining Condition | In this analysis, results were tabulated for the main study groups. | From Month 0 until Month 18 | 
| Number of Subjects With Any Pre-defined Changes in HIV Viral Load (VL) and CD4 T-cell Count | In this analysis, results were tabulated for the main study groups. | From Month 1 to Month 7 | 
| Number of Subjects With Any Significant Change in Antiretroviral Therapy (ART), Including Initiation of ART in ART-naïve Subjects, by HIV Status | In this analysis, results were tabulated by HIV status | From Month 0 to Month 18 | 
| Number of Subjects With Any AIDS-defining Condition, by HIV Status | In this analysis, results were tabulated by HIV status | From Month 0 to Month 18 | 
| Number of Subjects With Any Pre-defined Changes in HIV Viral Load (VL) and CD4 T-cell Count, by HIV Status | In this analysis, results were tabulated by HIV status. | From Month 1 to Month 7 | 
| Frequency of gE-specific CD4 T-cells | The analysis focused on CD4 T-cells expressing at least 2 cytokines (among interferon-gamma (IFN-g) , interleukin-2 (IL-2), tumour necrosis factor-alpha (TNF-a) and/or CD40 ligand (CD40L)) as determined by in vitro intracellular cytokine staining (ICS) at Month 7 in ART and non-ART cohorts presenting high CD4 counts at enrollment. | At Month 7 | 
| -Anti-gE Antibody (Ab) Concentrations | -Anti-gE antibody (Ab) concentrations were determined by Enzyme-Linked Immunosorbent Assay (ELISA) at Month 7 in ART and non-ART cohorts presenting high CD4 counts at enrolment. Antibody concentrations were presented as geometric mean concentrations (GMCs) and expressed in milli-international units per milliliter (mIU/mL). | At Month 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| -Frequencies of Varicella-Zoster Virus (VZV)- and gE-specific CD4 T-cells | The analysis focused on CD4 T cells expressing at least 2 cytokines (among IFN-g, IL-2, TNF-a and/or CD40L as determined by ICS at Months 0, 1, 2, 3, 6, 7 and 18 and tabulated for the main study groups. | At Month 0, 1, 2, 3, 6, 7 and 18 | 
| -Frequencies of Varicella-Zoster Virus (VZV)- and gE-specific CD4 T-cells, by HIV Status | The analysis focused on CD4 T-cells expressing at least 2 cytokines (among IFN-g, IL-2, TNF-a and/or CD40L as determined by ICS at Months 0, 1, 2, 3, 6, 7 and 18 and tabulated by HIV status. | At Months 0, 1, 2, 3, 6, 7 and 18 | 
| -Anti-VZV and Anti-gE Antibody Concentrations | Antibody concentrations were as determined by ELISA and tabulated for the main study groups. Anti-VZV and anti-gE antibody concentrations were presented as geometric mean concentrations (GMCs) and expressed in mIU/mL. | At Months 0, 1, 2, 3, 6, 7 and 18 | 
| -Anti-VZV and Anti-gE Antibody Concentrations, by HIV Status | Antibody concentrations were as determined by ELISA and tabulated by HIV status. Anti-VZV and anti-gE antibody concentrations were presented as geometric mean concentrations (GMCs) and expressed in mIU/mL. | At Months 0, 1, 2, 3, 6, 7 and 18 | 
| Number of Subjects With Any Herpes Zoster (HZ) Cases and Complications |  | From Month 0 until Month 18 | 
| CD4 Count | CD4 count was tabulated by HIV status. | At Screening Visit (up to 21 days prior to Month 0), Months 1, 2, 3, 6, 7 and 18 | 
| HIV VL | HIV VL was tabulated by HIV status, for subjects with a number of available results greater than or equal to (≥) 40 copies/mL. | At Screening Visit (up to 21 days prior to Month 0), Months 1, 2, 3, 6, 7 and 18 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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immunogenicity, vaccine, safety, HIV, Herpes Zoster