A Study to Assess Frailty of Subjects During ZOSTER-006 and ZOSTER-022

Study Overview
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Brief Summary
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As part of the ZOSTER-006 and ZOSTER-022 pivotal trials of the HZ/su vaccine, all study participants completed quality of life (QoL) questionnaires. The only questionnaires encoded into the data base were those from participants who developed a suspected shingles episode during the study. The purpose of this study is to allow for the encoding and analysis of questionnaires for all subjects enrolled in ZOSTER-006 and ZOSTER-022. The aim is to assess the baseline frailty of subjects enrolled in these studies and to investigate whether this population is representative of the general population.

Detailed Description
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As part of the study procedure, each subject enrolled in studies Zoster-006 and Zoster-022 was asked to complete two quality of life (QoL) questionnaires named respectively SF-36 and EQ-5D at predefined study time points. These questionnaires were to provide relevant information about the quality of life (functional status, ability to socialize, mental health, etc.) of subjects before they develop shingles Extracting some elements of the Quality of Life questionnaires (QoL), EQ-5D and SF-36, completed by all study subjects at baseline, and combining them with other medical history data allows attributing of frailty scores. Analyses pertaining to efficacy, safety and immunogenicity as per frailty score might be performed according to the methodology used in the ZOSTER-006 and ZOSTER-022 studies. Additionally, the data collected can be used to assess if some physical, physiological and/or psychological characteristics reported by the subjects before the onset of HZ would be predictive of HZ.

Official Title
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Observational Study to Assess Frailty of Subjects During ZOSTER-006 and ZOSTER-022 and HZ Efficacy, Immunogenicity and Safety of HZ/su by Frailty Status

Conditions
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Herpes Zoster

Intervention / Treatment
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* Other: Encoding of data collected in Zoster 006 and Zoster 022 studies


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All subjects who participated in the Zoster 006 and Zoster 022 trials. Subjects who died or were lost to follow-up during ZOSTER-006 and ZOSTER-022 will be considered for enrolment in ZOSTER-064 and their data/questionnaires up to that point will be used. Exclusion Criteria: Subjects who were excluded from all analyses from ZOSTER-006 and ZOSTER-022. This will include any subject eliminated following deviations from GCP compliance. Subjects who developed a suspected HZ case during ZOSTER-006 and ZOSTER-022 (since their QoL questionnaires were encoded in the eCRF for ZOSTER-006 and ZOSTER-022).

Ages Eligible for Study
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Minimum Age: 50 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Overall Group<br>Adults aged ≥50 years of age in the Zoster-064 TVC who received herpes zoster subunit (HZ/su) vaccine or Placebo in Zoster-006/022 study | Other: Encoding of data collected in Zoster 006 and Zoster 022 studies<br>* Not applicable (disease epidemiology study)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects by Frailty Status, at Baseline | Frailty status was measured in relation to the accumulation of deficits using a Frailty Index (FI) adapted from the model proposed by Mitnitski et al. [Mitnitski, 2001]. The different aspects of frailty composing the FI were assessed through the medical history and components of the Short Form 36 Questionnaire (SF-36) and EuroQol (EQ)-5D questionnaires recorded pre-vaccination Dose 1 (in the study ZOSTER-006[NCT01165177] and ZOSTER-022[NCT01165229]). If the FI was less than or equal to 0.08, the subject was classified as Non-Frail. If the score was greater than 0.08 but less than or equal to 0.25, the subject was classified as pre-frail. If the score was greater than 0.25, the subject was classified as Frail. Subjects without a FI score were classified as unknown. | At Baseline (Month 0) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Distribution of Short Form 36 (SF-36) Questionnaire Scale Scores, by Country | The mean and standard deviation of the SF-36 Questionnaire scale scores are presented for each time point. The SF-36 is a multi-purpose health survey with 36 questions underlying the construction of 8 scales [Ware, 2001]: Physical Functioning (PF), Role Physical (RP), Bodily Pain (BP), General Health (GH), Vitality (VT), Social Functioning (SF), Role Emotional (RE) and Mental Health (MH). All but one of the 36 items (self-reported health transition) are used to score the eight SF-36 scales. Each item is used in scoring only one scale. Scale scores are constructed following the summated ratings and standardized SF-36 scoring algorithms. The SF-36 scores range from 0 to 100, with high scores indicating high levels of functioning/quality of life. | At Month 0, 14, 26 and 38 | 
| Distribution of EuroQol (EQ)-5D Questionnaire Scale Scores, by Country | The EQ-5D questionnaire is a generic measure of health status that provides a simple descriptive profile and a single index value. The EQ-5D defines health in terms of mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each item has 3 possible responses (No symptoms, Moderate symptoms, Extreme symptoms). The 5 items are then combined to generate health profiles that are subsequently converted to a continuous single index utility score using a one to one matching. Country or region-specific value sets are used for the score conversion. The scores range from less than 0 (where 0 is the value of a health state equivalent to dead) to 1 (the value of full health), with higher scores indicating higher health utility. The EQ-5D also contains a visual analogue scale (VAS). The VAS records the respondent's self-rated health on a vertical scale, ranging from 0(worst imaginable health state) to 100(best imaginable health state). | At Month 0, 14, 26 and 38 | 
| Incidence Rate (Per 1000 Person-years) of Confirmed Herpes Zoster (HZ) Cases, by Frailty Status | Incidence rate (IR) of confirmed Herpes zoster (HZ) cases with 95% Confidence Interval (CI) calculated as the number of cases per 1000 person-years : numerator = number of confirmed HZ cases reported during the follow-up (FU) period at risk; denominator = total Person-years at risk, i.e. sum of FU periods at risk expressed in years until first confirmed HZ cases or occurrence of treatment for relapse. A suspected HZ case defined as (1) new rash characteristic of HZ (e.g., unilateral, dermatomal and accompanied by pain broadly defined to include allodynia, pruritus or other sensations), or vesicular rash suggestive of Varicella Zoster Virus (VZV) infection regardless of the distribution, and no alternative diagnosis; or (2) clinical presentation and specific laboratory findings suggestive of VZV infection in the absence of HZ or VZV rash. A suspected case of HZ was confirmed either by PCR or by the HZ Ascertainment Committee (HZAC), consisting of physicians with HZ expertise. | During the entire study period (3 to 5 year period following Day 0) | 
| Herpes Zoster Burden of Illness Score, by Frailty Status | Zoster Brief Pain Inventory (ZBPI) Burden of Illness (BOI) score was calculated as the sum of the ZBPI worst pain scores for all subjects in the group divided by the total follow-up time (Person-years). HZ Burden of Illness score for subjects was calculated from the Zoster Brief Pain Inventory (ZBPI), for each confirmed HZ cases responding to the worst pain question in both ZOSTER-006 and ZOSTER-022, and defined as the area under the curve of confirmed HZ-associated pain plotted against time during the 182-day period after the onset of the case. Subjects who developed HZ presented burden-of-illness scores ranging from 0 up to, theoretically, 1820. A score of 0 is recorded for subjects in whom HZ did not develop during the study period. Subjects who had a confirmed Zoster episode but who did not have at least 1 ZBPI assessment were excluded from the analysis. | During the entire study period (3 to 5 year period following Day 0) | 
| Number of Subjects With Any and Grade 3 Solicited Local Symptoms, by Frailty Status | 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. | Within 7 days (Days 0-6) after each vaccination | 
| Number of Subjects With Any, Grade 3 and Related Solicited General Symptoms, by Frailty Status | Assessed solicited general symptoms were, fatigue, fever [defined as axillary temperature equal to or above 37.5 degrees Celsius (°C)], headache, myalgia, shivering and gastro-intestinal (GI) symptoms(nausea, vomiting, diarrhoea and/or abdominal pain) 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. | Within 7 days (Days 0-6) after each vaccination | 
| Number of Subjects With Any, Grade 3 and Related Unsolicited Adverse Events (AEs), by Frailty Status | An unsolicited AE covered 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 and Related Serious Adverse Events (SAEs), by Frailty Status | 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. Related SAEs were those considered vaccine-related by the investigator. | From Month 0 to Month 14 | 
| Number of Subjects With SAEs Related to Study Participation or to a Concurrent GSK Medication/Vaccine, by Frailty Status | 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. Related SAEs throughout the entire study period by frailty status were reported for SAEs considered related to study participation or to a concurrent GSK medication/vaccine. | During the entire study period (3 to 5 year period following Day 0) | 
| Number of Subjects With Any Fatal Serious Adverse Events (SAEs), by Frailty Status | Serious adverse events (SAEs) assessed include medical occurrences that result in death. | During the entire study period (3 to 5 year period following Day 0) | 
| Number of Subjects With Any and Related Potential Immune-mediated Diseases (pIMDs), by Frailty Status | 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 related to the vaccination. | During the entire study period (3 to 5 year period following Day 0) | 
| Anti-glycoprotein E (Anti-gE) Antibody (Ab) Concentrations, by Frailty Status, in a Subset of Subjects | Anti-gE Ab concentrations as determined by Enzyme-linked Immunosorbent Assay (ELISA), in a subset of subjects. The assay cut-off is 97 milli-international units (mIU)/mL. | Pre-vaccination at Month 0, and post second dose at Months 3, 14, 26 and 38 | 
| Anti-Varicella Zoster Virus (Anti-VZV) Antibody (Ab) Concentrations, by Frailty Status, in a Subset of Subjects | Anti-VZV Ab concentrations as determined by Enzyme-linked Immunosorbent Assay (ELISA), in a subset of subjects. The assay cut-off is 25 mIU/mL. | Pre-vaccination at Month 0, and post second dose at Months 3, 14, 26 and 38 | 

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