Study to Assess the Safety and Immunogenicity of GlaxoSmithKline (GSK) Biologicals' Herpes Zoster Subunit (HZ/su) Vaccine in Adults Aged 18 Years and Older With Blood Cancers

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and immunogenicity of GSK Biologicals' vaccine GSK1437173A in subjects aged 18 years and older with blood cancers. The study will evaluate safety-related events and antibody and cellular immune responses to the study vaccine, as compared to placebo.

Detailed Description
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Amendment to protocol posting: Increase in sample size, update of country/region-specific information (Sections 5, 6 and 9). Promotion of secondary to primary objective; related update of primary and secondary outcome measures (Sections 4 and 7).

Official Title
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Study to Evaluate Safety and Immunogenicity of GSK Biologicals' Herpes Zoster Vaccine GSK1437173A in Adults Aged 18 Years and Older With Haematologic Malignancies

Conditions
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Herpes Zoster

Intervention / Treatment
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* Biological: Herpes zoster vaccine (GSK 1437173A)
* Drug: 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. Written informed consent obtained from the subject. A male or female, aged 18 years or older at the time of study entry. Subject who has been diagnosed with one or more haematologic malignancies prior to the first vaccination and who is receiving, is scheduled to receive or has just finished immunosuppressive cancer therapy to treat this condition. Life expectancy greater than or equal to 12 months, as assessed by the investigator. Female subjects of non-childbearing potential may be enrolled in the study. Non-childbearing potential is defined as pre-menarche, current tubal ligation, hysterectomy, ovariectomy or post-menopause. Female subjects of childbearing potential may be enrolled inthe 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. Exclusion Criteria: Subject diagnosed with chronic lymphocytic leukaemia (CLL) who is receiving only oral cancer therapy (subject receiving intra-venous cancer therapy for CLL or intra-venous cancer therapy in combination with oral therapy may be enrolled). Subject receiving radiotherapy alone as treatment for his/her haematologic malignancy. Planned haematopoietic stem cell transplant (HCT) during the study period. (If a HCT occurred prior to enrolment in the study, the subject may not receive study vaccine until at least 50 days after the transplant procedure). Human immunodeficiency virus (HIV) infection by clinical history. 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. However, the investigational use of a registered product to treat the subject's underlying disease, is allowed. Previous vaccination against HZ or varicella within the 12 months preceding the first dose of study vaccine/placebo. Planned administration during the study of a HZ or varicella vaccine (including an investigational or non-registered vaccine) other than the study vaccine. Occurrence of a varicella or HZ episode by clinical history within the 12 months preceding the first dose of study vaccine/placebo. History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccine. Administration or planned administration of a live vaccine in the period starting 30 days before the first dose of study vaccine and ending 30 days after the last dose of study vaccine. Administration or planned administration of a non-replicating vaccine within 8 days prior to or within 14 days after either dose of study vaccine. Pregnant or lactating female. Female planning to become pregnant or planning to discontinue contraceptive precautions before Month 3 (i.e., 2 months after the last dose of study vaccine/placebo).

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: Vaccine Group<br>Subjects will receive the candidate HZ vaccine (GSK 1437173A). | Biological: Herpes zoster vaccine (GSK 1437173A)<br>* 2 doses administered intramuscularly (IM) in deltoid region of non-dominant arm. Dose 1 administered at Day 0. Dose 2 administered 1-2 months post Dose 1.<br>|
| Placebo Comparator: Placebo Group<br>Subjects will receive the placebo vaccine. | Drug: Placebo<br>* 2 doses administered intramuscularly (IM) in deltoid region of non-dominant arm. Dose 1 administered at Day 0. Dose 2 administered 1-2 months post Dose 1.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vaccine Response Rates (VRR) for Anti-glycoprotein E (Anti-gE) Antibody Concentrations | Vaccine response rate refers to the percentage of subjects with a vaccine response, as determined by Enzyme-Linked Immunosorbent Assay (ELISA). Vaccine response was defined as: For initially seronegative subjects, antibody concentration at Month 2 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 Month 2 ≥ 4 fold the pre-vaccination antibody concentration. This analysis was performed on subjects with haematologic malignancies excluding subjects with Non-Hodgkin B-cell Lymphoma and Chronic Lymphocytic Leukaemia. | At Month 2 | 
| Adjusted Geometric Mean Concentration of Anti-gE Antibodies | The Adjusted geometric mean concentration was measured in all subjects excluding those with Non-Hodgkin B-cell Lymphoma and Chronic Lymphocytic Leukaemia. | At Month 2 | 
| 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 activity. 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 Days With Solicited Local Symptoms | Solicited local symptoms: pain, redness, swelling and their number of days were recorded after each vaccination dose. | Within the 7-day (Days 0-6) post-vaccination period | 
| 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 fever [defined as oral, axillary or tympanic route measured 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. | During the 7-day (Days 0-6) post-vaccination period following each dose and across doses | 
| Number of Days With Solicited General Symptoms | Solicited general symptoms: fatigue, gastrointestinal symptoms, headache, myalgia, shivering, temperature and their number of days were recorded after each vaccination dose. | Withing the 7-day (Day 0-6) post-vaccination period | 
| Number of Subjects With Any, Grade 3 and Related 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. It also included 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 the 30-day (Days 0-29) post-vaccination period | 
| Number of Subjects With Serious Adverse Events (SAEs) | A Serious adverse event (SAE) is any untoward medical occurrence that result in death, is life threatening, requires hospitalisation or prolongation of existing hospitalisation, results in disability/incapacity, or is a congenital anomaly/birth defect in the offspring of a study subject. Related = SAEs assessed by the investigator as causally related to the study vaccination | From first vaccination up to 30 days post last vaccination | 
| Number of Subjects Reporting Any and Related Potential Immune-mediated Diseases (pIMDs) | Potential immune-mediated diseases (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. Related = pIMds assessed by the investigator as causally related to the study vaccination | From first vaccination up to 30 days post last vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vaccine Response Rate (VRR) for Anti-gE Antibody Concentrations | Vaccine response rate refers to the percentage of subjects with a vaccine response, as determined by ELISA. Vaccine response was defined as: For initially seronegative subjects, antibody concentration at Month 2 ≥ 4 fold the cut-off for Anti-gE (4x97 mIU/mL). For initially seropositive subjects, antibody concentration at Month 2 ≥ 4 fold the pre -vaccination antibody concentration. This analysis was performed on subjects with haematologic malignancies, excluding subjects with Non-Hodgkin B-cell Lymphoma. | At Month 2 | 
| Anti-gE Antibody Concentrations | Antibody concentrations were determined by ELISA, presented as geometric mean concentrations (GMCs) and expressed in milli-international units per milliliter (mIU/mL).This parameter was assessed in subjects with haematologic malignancies, excluding subjects with Non-Hodgkin B-cell Lymphoma. | At Month 2 | 
| Time to Occurrence of Any Confirmed HZ Case | Time to occurrence of any confirmed HZ case is expressed in terms of incidence rate of subjects with at least one event. Hence, person-year rate = number of episodes (n)/ sum of follow-up period (censored at the first occurrence of an event) expressed in years (T[year)]). Follow-up period starts Day 1 of vaccination. Any clinically suspected case of HZ (defined as (1) a new rash characteristic of HZ (e.g., unilateral, dermatomal and accompanied by pain broadly defined to include allodynia, pruritus or other sensations), or a vesicular rash suggestive of Varicella Zoster Virus (VZV) infection regardless of the distribution, and no alternative diagnosis; or (2) a clinical presentation (symptoms and/or signs) and specific laboratory findings suggestive of VZV infection in the absence of characteristic HZ or VZV rash.) The endpoint is confirmed in two ways: (1) By Polymerase Chain Reaction (PCR) or (2) By the HZ Ascertainment Committee. The PCR is used as primary classification method. | From Month 0 until study end (Month 13) | 
| Anti-gE Antibody Concentrations | Antibody concentrations were determined by ELISA, presented as geometric mean concentrations (GMCs) and expressed in milli-international units per milliliter (mIU/mL). This parameter was assessed in all vaccinated subjects. | At Months 0, 1, 2 and 13 | 
| Vaccine Response Rate (VRR) for Anti-gE Antibody Concentrations | Vaccine response rate refers to the percentage of subjects with a vaccine response, as determined by ELISA. Vaccine response was defined as: For initially seronegative subjects, antibody concentration at Month 2 ≥ 4 fold the cut-off for anti-gE (4x97 mIU/mL). For initially seropositive subjects, antibody concentration at Month 2 ≥ 4 fold the pre -vaccination antibody concentration. Vaccine response was measured in all subjects. | At Months 1, 2 and 13 | 
| Frequency of gE -Specific Cluster of Differentiation 4 (CD4) [2+] T-cells Expressing at Least 2 Activation Markers | Among markers expressed were interferon-gamma (IFN-γ), interleukin-2 (IL-2), tumour necrosis factor-alpha (TNF-α) and cluster of differentiation 40 ligand (CD40L), as determined by in vitro intracellular cytokine staining (ICS). | At Months 0, 1, 2 and 13 | 
| Vaccine Response Rates (VRR) for gE-specific CD4 [2+] T-cells, Expressing at Least 2 Activation Markers | Among markers expressed were IFN-γ, IL-2, TNF-α and CD40L, as 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/106 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 1, 2 and 13 | 
| Number of Subjects With Serious Adverse Events (SAEs) | A Serious adverse event (SAE) is any untoward medical occurrence that result in death, is life threatening, requires hospitalisation or prolongation of existing hospitalisation, results in disability/incapacity, or is a congenital anomaly/birth defect in the offspring of a study subject. Related = SAEs assessed by the investigator as causally related to the study vaccination | From first vaccination at Month 0 up to study end at Month 13 | 
| Number of Subjects Reporting Any Potential Immune-mediated Diseases (pIMDs) | Potential immune-mediated diseases (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 at Month 0 up to study end at Month 13 | 
| Geometric Mean Concentrations (GMCs) of Anti-gE Antibodies | GMCs of anti-gE antibodies were tabulated per study group and HZ confirmed/non-confirmed status and expressed in milli-international units per milliliter (mIU/mL). | At Months 0 and 2 | 
| Mean Geometric Increase (MGI) of Anti-gE Antibody ELISA Concentrations | MGI was tabulated per study group and HZ confirmed/non-confirmed status. MGI was defined as the Geometric mean of the within subject ratios of the post-vaccination reciprocal anti-gE concentration to the Month 0 reciprocal anti-gE concentration. | At Month 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immunogenicity, Safety, Herpes zoster, Vaccination, Haematologic malignancies