Immunogenicity and Safety of GlaxoSmithKline (GSK) Biologicals' Herpes Zoster Subunit (HZ/su) Vaccine in Adults 18 Years of Age or Older With Renal Transplant

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the immunogenicity and safety of GSK Biologicals' HZ/su vaccine administered on a 0- and 1- to 2-months schedule in adults 18 years of age or older who are receiving chronic immunosuppressive therapy.

Official Title
-----------------
Observer-blind Study to Evaluate Immunogenicity and Safety of GSK Biologicals' Herpes Zoster Subunit (HZ/su) Vaccine GSK1437173A in Adults 18 Years of Age or Older With Renal Transplant

Conditions
-----------------
Herpes Zoster

Intervention / Treatment
-----------------
* Biological: Herpes Zoster vaccine GSK1437173A
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects who, in the opinion of the investigator, can and will comply with the requirements of the protocol. A male or female, aged 18 years or older and having reached the age of legal consent, on the date the informed consent is signed. Written informed consent obtained from the subject. Subject who has received an ABO compatible allogeneic renal transplant. Subject receiving maintenance immunosuppressive therapy for the prevention of allograft rejection for a minimum of one month (30 days) prior to the first vaccination. Subject without an episode of allograft rejection over the previous three months (90 days) prior to the first vaccination. Subject with stable renal function, stability defined as: less than 20% variability between last two creatinine measurements or calculated GFR or in the opinion of the investigator after investigator review of more than the last two creatinine measurements or calculated GFRs. Subject not less than 4 months (120 days) and not more than 18 months (547 days) after allograft transplantation at the time of the first vaccination. Subjects with multiple dialysis options (peritoneal and/or more than one anatomical access site for haemodialysis) in the event acute or chronic dialysis is needed. 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 the first vaccination, and has agreed to continue adequate contraception during the primary treatment period and for 2 months after completion of the vaccination series. Exclusion Criteria: Any primary kidney disease with a high incidence of recurrent primary kidney disease. Evidence of recurrent primary kidney disease within the current allograft. Previous allograft loss secondary to recurrent primary kidney disease. Multiple kidney transplants are allowed if the reason for a previous allograft's loss is not recurrent primary kidney disease. More than one organ transplanted (i.e. kidney-liver, double kidney or kidney-other organ(s) transplanted). History of events that, in the opinion of the investigator, may put subject at increased risk for chronic allograft dysfunction (e.g. delayed graft function, peri-operative complications). Histologic reports of chronic allograft injury (e.g. transplant glomerulopathy, arteriopathy, C4d deposition). Evidence of significant proteinuria in the opinion of the investigator. Panel reactive antibody score (PRA or cPRA) that is unknown at the time of transplant. Any autoimmune or potential immune-mediated disease including primary kidney disease. Use of anti-CD20 or other B-cell monoclonal antibody agents (e.g., rituximab) as induction, maintenance and/or therapeutic immunosuppressive therapy for the prevention of allograft rejection within 9 months (274 days) of first dose of study vaccine/placebo. Use of any investigational or non-registered product other than the study vaccine within 30 days preceding the first dose of study vaccine/placebo, or planned use during the study period. Concurrent or planned participation in another clinical study, at any time during the study period, which has exposed or will expose the subject to an investigational or a non-registered product Administration or planned administration of a live vaccine within 30 days prior to the first dose of study vaccine and ending 30 days after the last dose of study vaccine, or, administration or planned administration of a non-replicating vaccine within 8 days prior to or within 14 days after either dose of study vaccine. Planned administration during the study of a varicella or HZ vaccine other than the study vaccine. Previous vaccination against HZ or varicella within the 12 months preceding the first dose of study vaccine/placebo. Occurrence of varicella or HZ per clinical history, within the 12 months preceding the first dose of study vaccine/placebo. Failure to fully complete the 7-day pre-vaccination diary card distributed at the Pre-vaccination visit. Evidence or high suspicion, in the opinion of the investigator, of noncompliance or nonadherence to use of induction and/or maintenance immunosuppressive therapies. Any confirmed or suspected HIV, primary immunodeficiency disease, disseminated or untreated malignancy, or systemic infection. History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccine or study material and equipment. Any condition which, in the judgment of the investigator, would make intramuscular injection unsafe. Any other condition that, in the opinion of the investigator, might interfere with the evaluations required by the study. Acute disease and/or fever at the time of vaccination. Fever is defined as temperature ≥ 37.5°C /99.5°F by oral route. The preferred route for recording temperature in this study will be oral. Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory infection) without fever may be enrolled at the discretion of the investigator. Pregnant or lactating female. Female planning to become pregnant or planning to discontinue contraceptive precautions (if of childbearing potential) before Month 3.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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, aged 18 years or older, received 2 doses of the GSK 1437173A vaccine, adjuvanted with AS01B at Day 0, and Month 1, administered intramuscularly, in the deltoid muscle of an arm. | Biological: Herpes Zoster vaccine GSK1437173A<br>* 2 doses administered intramuscularly (IM) in the deltoid region of the non-dominant arm.<br>|
| Placebo Comparator: Placebo Group<br>Subjects, aged 18 years or older, received 2 doses of Placebo (lyophilised sucrose reconstituted with saline [NaCl] solution) at Day 0, and Month 1, administered intramuscularly, in the deltoid muscle of an arm. | Drug: Placebo<br>* 2 doses administered intramuscularly (IM) in the deltoid region of the non-dominant arm.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With a Vaccine Response for Anti-glycoprotein E (gE) Humoral Immunogenicity | Vaccine response was defined as: For initially seronegative subjects, antibody concentration at post-vaccination greater than or equal to (≥) 4 fold the cut-off for Anti-gE (4x97 milli-international units per milliliter [mIU/ml]); For initially seropositive subjects, antibody concentration at post-vaccination ≥ 4 fold the pre-vaccination antibody concentration. Vaccine response was determined by Enzyme-Linked ImmunoSorbent Assay (ELISA). | At Month 2. | 
| Number of Subjects With 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 when limb was moved, which prevented everyday activities. Grade 3 redness/swelling = redness/swelling spreading beyond 100 millimeters (mm) of injection site. | Within 7 days (Days 0-6) after each dose and across doses. | 
| Days With Solicited Local Symptoms | Assessed solicited local symptoms were pain, redness and swelling. | Within 7 days (Days 0-6) after each dose and overall/dose | 
| Number of Subjects With Solicited General Symptoms | Assessed solicited general symptoms were fatigue, gastrointestinal symptoms, headache, myalgia, shivering and fever [defined as axillary temperature equal to or above 37.5 degrees Celsius (°C)] . 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. Gastrointestinal symptoms (Gastro. sympt.) included nausea, vomiting, diarrhoea and/or abdominal pain. | Within 7 days (Days 0-6) after each dose and across doses | 
| Days With Solicited General Symptoms | Assessed solicited general symptoms were fatigue, gastrointestinal symptoms, headache, myalgia, shivering and fever [defined as axillary temperature equal to or above 37.5 degrees Celsius (°C)]. | Within 7 days (Days 0-6) after each dose and overall/dose | 
| Number of Subjects With Unsolicited Symptoms (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 Any Potential Immune-mediated Diseases (pIMDs) | pIMDs are a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune aetiology | From first vaccination (Month 0) up to 1 month post last vaccination (Month 2). | 
| Number of Subjects With Any and Related Serious Adverse Events (SAEs) | SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongatoion of hospitalization, or result in disability /incapacity. Related = SAE assessed by the investigator as related to the vaccination. | From first vaccination (Month 0) up to 1 month post last vaccination (Month 2). | 
| Number of Subjects With Renal Allograft Rejection | Renal allograft rejection was confirmed through biopsy. | From the first vaccination (Month 0) up to 1 month post last vaccination (Month 2). | 
| Number of Subjects With Changes in Allograft Function | Allograft function was indicated by the increase in levels of serum creatinine (≥ 1.20, ≥ 1.50, ≥ 1.75 or ≥ 2 fold increase). The number of subjects with declining allograft function, as determined by serum creatinine measurements post-vaccination (up to 30 days post-last vaccination) compared to pre-vaccination were presented. | From the first vaccination (Month 0) up to 1 month post last vaccination (Month 2). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-gE Antibody Concentrations | Varicella Zoster Virus (VZV) gE antibody Immunoglobulin G concentrations were determined by ELISA assay, presented as geometric mean concentrations (GMCs) and expressed in milli-international units per milliliter (mIU/mL). The reference seropositivity cut-off value was ≥ 97 mIU/mL. | At Months 0, 1, 2, 7 and 13 | 
| Number of Subjects With a Vaccine Response for Anti-gE Humoral Immunogenicity | Vaccine response was defined as: For initially seronegative subjects, antibody concentration at post-vaccination greater than or equal to (≥) 4 fold the cut-off for Anti-gE (4x97 mIU/mL); For initially seropositive subjects, antibody concentration at post-vaccination ≥ 4 fold the pre-vaccination antibody concentration. Vaccine response was determined by ELISA. | At Months 1, 7 and 13 | 
| Frequencies of gE-specific Cluster of Differentiation 4 (CD4+) T-cells | Descriptive statistics of gE-specific CD4+ T-cells, expressing at least two activation markers (from among interferon gamma [IFN-γ], interleukin-2 [IL-2], tumour necrosis factor alpha [TNF-α] and cluster of differentiation 40-ligand [CD40L]) were tabulated, as determined by in vitro Intracellular Cytokine Staining (ICS). | At Months 0, 2 and 13 | 
| Number of Subjects With a Vaccine Response for gE-specific CD4+ T-cells | Vaccine response for gE-specific CD4+ T-cells expressing at least two activation markers (from among IFN-γ, IL-2, TNF-α and CD40L), was determined by in vitro ICS. Vaccine response was defined as: For initially subjects with pre-vaccination T-cell frequencies below the threshold, at least a 2-fold increase as compared to the threshold (2x<320> Events/10 million CD4+ T-cells); For initially subjects with pre-vaccination T-cell frequencies above the threshold, at least a 2-fold increase as compared to pre-vaccination T-cell frequencies. | At Months 2 and 13 | 
| Number of Subjects With Any and Related SAEs | SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity. Related = SAE assessed by the investigator as related to the vaccination. | From 1 month post last vaccination (Month 2) until study end (Month 13). | 
| Number of Subjects With Any pIMDs | pIMDs are a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune aetiology. | From 1 month post last vaccination (Month 2) until study end (Month 13). | 
| Number of Subjects With Renal Allograft Rejection | Renal allograft rejection was confirmed through biopsy. | From 1 month post last vaccination (Month 2) until study end (Month 13). | 
| Number of Subjects With Changes in Allograft Function | Allograft function was indicated by the increase in levels of serum creatinine (≥ 1.20, ≥ 1.50, ≥ 1.75 or ≥ 2 fold increase). The number of subjects with declining allograft function, as determined by serum creatinine measurements post-vaccination (from 30 days post-last vaccination up to study end) compared to pre-vaccination were presented. | From 1 month post last vaccination (Month 2) until study end (Month 13) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Immunocompromised, Safety, ≥ 18 years of age, Renal transplant, Adults, Immunosuppressed, Immunogenicity, Herpes zoster