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    Clinical Trial Results:
    A phase II/III, randomised, observer-blind, placebo-controlled, multicentre, clinical trial to assess the immunogenicity and safety of GSK Biologicals’ herpes zoster HZ/su candidate vaccine when administered intramuscularly on a 0 and 1 to 2 months schedule to adults ≥18 years of age with solid tumours receiving chemotherapy.

    Summary
    EudraCT number
    		 2012-002966-11
    Trial protocol
    		 ES   GB   CZ  
    Global end of trial date

    Results information
    Results version number
    		 v1
    This version publication date
    02 Jul 2016
    First version publication date
    02 Jul 2016
    Other versions
    		 v2 , v3

    Trial information

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    Trial identification
    Sponsor protocol code
    116427
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01798056
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline Biologicals
    Sponsor organisation address
    Rue de l’Institut 89, Rixensart, Belgium, B-1330
    Public contact
    Clinical Trials Call Center, GlaxoSmithKline Biologicals, 44 2089904466, GSKClinicalSupportHD@gsk.com
    Scientific contact
    Clinical Trials Call Center, GlaxoSmithKline Biologicals, 44 2089904466, GSKClinicalSupportHD@gsk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    23 Apr 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Jun 2015
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    - To evaluate anti-gE humoral immune responses at Month 2, following a two-dose administration of the HZ/su vaccine, as compared to placebo in subjects with solid tumours receiving chemotherapy (PreChemo Groups only). Criteria to be used: The objective is met if the lower limit of the 95% confidence interval (CI) of the Geometric Mean (GM) ratio (HZ/su PreChemo group over Placebo PreChemo group) in anti-gE ELISA antibody concentrations is greater than 3. -To evaluate the safety and reactogenicity following administration of the HZ/su vaccine as compared to placebo up to 30 days post last vaccination in subjects with solid tumours receiving chemotherapy.
    Protection of trial subjects
    All subjects were supervised for 30 min after vaccination/product administration with appropriate medical treatment readily available. Vaccines/products were administered by qualified and trained personnel. Vaccines/products were administered only to eligible subjects that had no contraindications to any components of the vaccines/products. Subjects were followed-up for 30 days after the last vaccination/product administration.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Mar 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 170
    Country: Number of subjects enrolled
    United Kingdom: 30
    Country: Number of subjects enrolled
    Czech Republic: 5
    Country: Number of subjects enrolled
    France: 20
    Country: Number of subjects enrolled
    Korea, Republic of: 35
    Country: Number of subjects enrolled
    Canada: 6
    Worldwide total number of subjects
    266
    EEA total number of subjects
    225
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    192
    From 65 to 84 years
    72
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 During the screening the following steps occurred: check for inclusion/exclusion criteria, contraindications/precautions, medical history of the subjects and signing informed consent forms.

    Pre-assignment period milestones
    Number of subjects started
    		 266
    Number of subjects completed
    		 232

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 No vaccination received: 34
    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind [1]
    Roles blinded
    		 Subject, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 GSK1437173A Group
    Arm description
    		 Subjects receiving the adjuvanted GSK1437173A vaccine according to a 0, 1-2 month schedule.
    Arm type
    		 Experimental

    Investigational medicinal product name
    GSK 1437173A
    Investigational medicinal product code
    Other name
    HZ/su vaccine
    Pharmaceutical forms
    Powder and solvent for suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The vaccine was administered intramuscularly into the deltoid muscle of the non-dominant arm.

    Arm title
    		 Placebo Group
    Arm description
    		 Subjects receiving saline placebo according to a 0, 1-2 month schedule.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Saline solution
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The placebo was administered intramuscularly into the deltoid muscle of the non-dominant arm.

    Notes
    [1] - The roles blinded appear to be inconsistent with a double blind trial.
    Justification: This trial was blinded as concerns the subjects, the caregivers and the outcomes assessors.
    Number of subjects in period 1 [2]
    		GSK1437173A Group Placebo Group
    Started
    117
    115
    Completed
    102
    107
    Not completed
    15
    8
         Consent withdrawn by subject
    11
    5
         Adverse event, non-fatal
    3
    2
         Unspecified
    1
    1
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Some subjects enrolled in the study did not receive any vaccination and were eliminated before starting.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    GSK1437173A Group
    Reporting group description
    		 Subjects receiving the adjuvanted GSK1437173A vaccine according to a 0, 1-2 month schedule.

    Reporting group title
    Placebo Group
    Reporting group description
    		 Subjects receiving saline placebo according to a 0, 1-2 month schedule.

    Reporting group values
    		 GSK1437173A Group Placebo Group Total
    Number of subjects
    		 117 115 232
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.1 ( 10.8 ) 58.5 ( 11.7 ) -
    Gender categorical
    Units: Subjects
        Female
    		 70 69 139
        Male
    		 47 46 93

    End points

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    End points reporting groups
    Reporting group title
    GSK1437173A Group
    Reporting group description
    		 Subjects receiving the adjuvanted GSK1437173A vaccine according to a 0, 1-2 month schedule.

    Reporting group title
    Placebo Group
    Reporting group description
    		 Subjects receiving saline placebo according to a 0, 1-2 month schedule.

    Subject analysis set title
    HZ/su-PreChemo
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects receiving the adjuvanted HZ/su vaccine, with the first vaccination at least 10 days (up to 1 month) before the start of a chemotherapy cycle.

    Subject analysis set title
    Placeb-PreChemo
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects receiving saline placebo, with the first vaccination at least 10 days (up to 1 month) before the start of a chemotherapy cycle.

    Primary: Adjusted geometric means (GMC) of HZ/su over placebo for anti-glycoprotein E (gE) antibody ELISA concentrations in PreChemo Groups only

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    End point title
    		 Adjusted geometric means (GMC) of HZ/su over placebo for anti-glycoprotein E (gE) antibody ELISA concentrations in PreChemo Groups only
    End point description
    End point type
    Primary
    End point timeframe
    At Month 2
    End point values
    		 HZ/su-PreChemo Placeb-PreChemo
    Number of subjects analysed
    65
    76
    Units: EL.U/mL
    geometric mean (confidence interval 95%)
        Adjusted GMC of antibody titers
    24501.57 (19051.99 to 31509.94)
    1056.77 (990.37 to 1127.62)
    Statistical analysis title
    		 Adjusted GMC ratio
    Statistical analysis description
    The analysis evaluated the anti-gE humoral immune responses at Month 2, following a two-dose administration of the HZ/su vaccine, as compared to placebo in subjects with solid tumours receiving chemotherapy (PreChemo Groups only). Criteria used: The objective is met if the lower limit of the 95% confidence interval (CI) of the Geometric Mean (GM) ratio (HZ/su PreChemo group over Placebo PreChemo group) in anti-gE ELISA antibody concentrations is greater than 3.
    Comparison groups
    HZ/su-PreChemo v Placeb-PreChemo
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 < 0.0001
    Method
    		 Adjusted GMC ratio
    Parameter type
    		 Ratio
    Point estimate
    23.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 17.9
         upper limit
    		 30
    Notes
    [1] - Difference of means between vaccines and placebo were calculated together with 2-sided confidence intervals and back-transformed to the original units to provide GMCs and GM ratios.

    Secondary: Number of subjects with anti-gE antibody concentrations as determined by ELISA above the cut-off value (97 mIU/ml)

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    End point title
    		 Number of subjects with anti-gE antibody concentrations as determined by ELISA above the cut-off value (97 mIU/ml)
    End point description
    End point type
    Secondary
    End point timeframe
    At Month 2
    End point values
    		 GSK1437173A Group Placebo Group
    Number of subjects analysed
    87
    98
    Units: Subjects
        Subjects
    87
    97
    No statistical analyses for this end point

    Secondary: GMCs for anti-Varicella Zoster Virus (VZV) gE antibodies

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    End point title
    		 GMCs for anti-Varicella Zoster Virus (VZV) gE antibodies
    End point description
    End point type
    Secondary
    End point timeframe
    At Month 2
    End point values
    		 GSK1437173A Group Placebo Group
    Number of subjects analysed
    87
    98
    Units: mIU/mL
    geometric mean (confidence interval 95%)
        GMCs
    18291.7 (14432.1 to 23183.5)
    1060.5 (873.9 to 1287.1)
    No statistical analyses for this end point

    Secondary: Number of subjects with vaccine responses for anti-gE antibody ELISA concentrations

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    End point title
    		 Number of subjects with vaccine responses for anti-gE antibody ELISA concentrations
    End point description
    Vaccine response defined as : For initially seronegative subjects, antibody concentration at post-vaccination ≥ 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
    End point type
    Secondary
    End point timeframe
    At Months 1 and 2
    End point values
    		 GSK1437173A Group Placebo Group
    Number of subjects analysed
    87
    94
    Units: Subjects
        Vaccine responders Month 1 [N=85, 93]
    73
    0
        Vaccine responders Month 2 [N=87, 94]
    75
    0
    No statistical analyses for this end point

    Secondary: Descriptive statistics of the frequency of gE-specific CD4[2+] T-cells

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    End point title
    		 Descriptive statistics of the frequency of gE-specific CD4[2+] T-cells
    End point description
    Descriptive statistics were tabulated for CD4[2+] cells, which are gE-specific CD4+ T-cells with at least 2 activation markers ([2+]) expressed from the activation markers IFN-γ, IL-2, TNF-α and CD40 L, as determined by intra-cellular staining (ICS) method.
    End point type
    Secondary
    End point timeframe
    At Months 0, 1 and 2
    End point values
    		 HZ/su-PreChemo Placeb-PreChemo
    Number of subjects analysed
    20
    25
    Units: CD4 T-cells per million T-cells
    median (inter-quartile range (Q1-Q3))
        CD4[2+] T-cells, Month 0 [N=20, 23]
    134.5 (42.8 to 329.7)
    112 (39.3 to 151.5)
        CD4[2+] T-cells, Month 1 [N=19, 25]
    498.1 (336.1 to 652.4)
    53.9 (1 to 179.4)
        CD4[2+] T-cells, Month 2 [N=20, 21]
    832.1 (536.2 to 1303.6)
    58.9 (22.7 to 139.4)
    No statistical analyses for this end point

    Secondary: Number of subjects with vaccine responses for gE-specific CD4[2+] T-cells

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    End point title
    		 Number of subjects with vaccine responses for gE-specific CD4[2+] T-cells
    End point description
    Vaccine response 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 (2x320 Events/10E6 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
    End point type
    Secondary
    End point timeframe
    At Months 1 and 2
    End point values
    		 HZ/su-PreChemo Placeb-PreChemo
    Number of subjects analysed
    19
    23
    Units: Subjects
        CD4[2+] T-cells, Month 1 [N=19, 23]
    5
    0
        CD4[2+] T-cells, Month 2 [N=19, 20]
    11
    0
    No statistical analyses for this end point

    Secondary: Number of subjects with unsolicited adverse events (AEs)

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    End point title
    		 Number of subjects with unsolicited adverse events (AEs)
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    During the 30-day (Days 0-29) post-vaccination period
    End point values
    		 GSK1437173A Group Placebo Group
    Number of subjects analysed
    117
    115
    Units: Subjects
        Subjects with any AEs
    100
    102
    No statistical analyses for this end point

    Secondary: Number (%) of subjects with serious adverse events (SAEs)

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    End point title
    		 Number (%) of subjects with serious adverse events (SAEs)
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    From the first dose up to 30 days post last vaccination period
    End point values
    		 GSK1437173A Group Placebo Group
    Number of subjects analysed
    117
    115
    Units: Subjects
        Subjects with any SAEs
    16
    14
    No statistical analyses for this end point

    Secondary: Number of subjects with any potential Immune Mediated Diseases (pIMDs)

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    End point title
    		 Number of subjects with any potential Immune Mediated Diseases (pIMDs)
    End point description
    End point type
    Secondary
    End point timeframe
    From first vaccination up to 30 days post last vaccination
    End point values
    		 GSK1437173A Group Placebo Group
    Number of subjects analysed
    117
    115
    Units: Subjects
        pIMDs
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Solicited symptoms during the 7-day post-vaccination period; Unsolicited AEs during the 30-day post-vaccination period; SAEs during the entire study period.
    Adverse event reporting additional description
    Individual SAEs remain blinded as long as the study is ongoing.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    HZ/su Group
    Reporting group description
    		 -

    Reporting group title
    Placebo Group
    Reporting group description
    		 -

    Serious adverse events
    		 HZ/su Group Placebo Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 117 (0.00%)
    0 / 115 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 HZ/su Group Placebo Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    115 / 117 (98.29%)
    106 / 115 (92.17%)
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    1 / 117 (0.85%)
    6 / 115 (5.22%)
         occurrences all number
    1
    6
    Headache
         subjects affected / exposed
    45 / 117 (38.46%)
    41 / 115 (35.65%)
         occurrences all number
    61
    52
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    11 / 117 (9.40%)
    13 / 115 (11.30%)
         occurrences all number
    12
    15
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    30 / 117 (25.64%)
    29 / 115 (25.22%)
         occurrences all number
    34
    33
    Chills
         subjects affected / exposed
    39 / 117 (33.33%)
    25 / 115 (21.74%)
         occurrences all number
    48
    30
    Fatigue
         subjects affected / exposed
    80 / 117 (68.38%)
    69 / 115 (60.00%)
         occurrences all number
    118
    109
    Mucosal inflammation
         subjects affected / exposed
    9 / 117 (7.69%)
    6 / 115 (5.22%)
         occurrences all number
    11
    8
    Pain
         subjects affected / exposed
    90 / 117 (76.92%)
    7 / 115 (6.09%)
         occurrences all number
    139
    7
    Pyrexia
         subjects affected / exposed
    22 / 117 (18.80%)
    9 / 115 (7.83%)
         occurrences all number
    23
    9
    Swelling
         subjects affected / exposed
    18 / 117 (15.38%)
    1 / 115 (0.87%)
         occurrences all number
    23
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    16 / 117 (13.68%)
    11 / 115 (9.57%)
         occurrences all number
    19
    11
    Diarrhoea
         subjects affected / exposed
    9 / 117 (7.69%)
    10 / 115 (8.70%)
         occurrences all number
    12
    10
    Dyspepsia
         subjects affected / exposed
    6 / 117 (5.13%)
    13 / 115 (11.30%)
         occurrences all number
    6
    13
    Gastrointestinal disorder
         subjects affected / exposed
    51 / 117 (43.59%)
    51 / 115 (44.35%)
         occurrences all number
    74
    63
    Nausea
         subjects affected / exposed
    31 / 117 (26.50%)
    28 / 115 (24.35%)
         occurrences all number
    36
    33
    Vomiting
         subjects affected / exposed
    10 / 117 (8.55%)
    14 / 115 (12.17%)
         occurrences all number
    10
    16
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    21 / 117 (17.95%)
    22 / 115 (19.13%)
         occurrences all number
    21
    22
    Erythema
         subjects affected / exposed
    43 / 117 (36.75%)
    1 / 115 (0.87%)
         occurrences all number
    58
    1
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    62 / 117 (52.99%)
    33 / 115 (28.70%)
         occurrences all number
    88
    45
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    9 / 117 (7.69%)
    5 / 115 (4.35%)
         occurrences all number
    12
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Nov 2012
    The primary objective for immunogenicity response (based on Geometric Mean [GM] ratios) following the HZ/su vaccination compared to placebo will now be evaluated only in the PreChemo Groups. The secondary objectives have now been qualified to evaluate immunogenicity in either the PreChemo Groups (Vaccine Response Rates [VRR] in anti-gE humoral immunogenicity responses and VRR and GM ratio in gE-specific Cellular-Mediated Immunity [CMI]) or in all study subjects (VRR and GM ratio in anti-gE humoral immunogenicity responses). The CMI sub-cohort will now only be recruited in the PreChemo Groups. The timepoint for evaluation of the primary objective for safety/reactogenicity has been reworded for clarity (‘up to 30 days post last vaccination’ instead of ‘up to month 2’).
    11 Aug 2014
    The cut-off of the gE-specific ELISA assay has been changed from 18 to 97 mIU/mL. The definition of the according-to-protocol (ATP) cohort for safety was updated. (Section 9.4.2) Statistical section was updated to describe the descriptive cell-mediated immune (CMI) response analysis, to clarify other descriptive analysis for immunogenicity and safety. (Section 9.5.3)

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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