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    Clinical Trial Results:
    A multicenter, open-label, phase 2 study of S-588410 as maintenance monotherapy after first-line platinum-containing chemotherapy in patients with advanced and/or metastatic bladder cancer.

    Summary
    EudraCT number
    2013-005274-22
    Trial protocol
    GB   BG  
    Global end of trial date
    02 Oct 2018

    Results information
    Results version number
    v2(current)
    This version publication date
    30 Aug 2019
    First version publication date
    28 Jul 2019
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Correction on the primary endpoint analysis, patients in the observation group were not part of the analysis.

    Trial information

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    Trial identification
    Sponsor protocol code
    1408P1921
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Shionogi & Co., Ltd
    Sponsor organisation address
    3-1-8 Doshomachi, Chuo-ku, Osaka, Japan, 541-0045
    Public contact
    Corporate Communications Department, Shionogi & Co., Ltd, +81 66209 7885, shionogiclintrial588410@shionogi.com
    Scientific contact
    Corporate Communications Department, Shionogi & Co., Ltd, +81 66209 7885, shionogiclintrial588410@shionogi.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
    Final
    Date of interim/final analysis
    25 Dec 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Nov 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Oct 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the specific cytotoxic T lymphocyte (CTL) response in human leukocyte antigen (HLA)-A*24:02 positive patients receiving S-588410 for 12 weeks.
    Protection of trial subjects
    Prior to initiation of the study, the sponsor discussed the ethical and scientific validity of the study protocol, sample informed consent form/written information for subjects, and other materials at an Ethics Committee on Clinical Trial of Shionogi. The study was conducted in compliance with the International Council for Harmonisation Good Clinical Practice (ICH GCP) and the guiding principles of the Declaration of Helsinki; and the Japanese Ordinance on GCP in the study sites in Japan. To maintain subject privacy, the initials and the assigned numbers of the subjects were used but not their names in case report forms (CRFs), study drug accountability records, study reports, and communications. To verify the data gathered on the CRFs and audit the data collection process, only monitors and auditors pre-assigned by the sponsor, and the regulatory authority(ies) could access to the subject’s original medical records. The subject’s confidentiality has been maintained and will not be made publicly available to the extent permitted by the applicable laws and regulations. The independent data monitoring committee (IDMC) was to assess the safety and efficacy data in the study and recommend whether or not to continue the study as necessary. The assessment by the IDMC was to be performed at the time when safety data were collected from the first 6 patients treated with S-588410 for 4 weeks and at the time when the study assessments were completed to all patients.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    17 Apr 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy, Scientific research
    Long term follow-up duration
    3 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    Japan: 73
    Worldwide total number of subjects
    81
    EEA total number of subjects
    8
    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)
    31
    From 65 to 84 years
    48
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    This was a multicenter study conducted at 62 sites, including 53 sites in Japan, 5 sites in the United Kingdom, 3 sites in France, and 1 site in Bulgaria.

    Pre-assignment
    Screening details
    In the Screening Period of 28 days prior to enrollment, potential patients who provided written informed consent were assessed for their eligibility.

    Pre-assignment period milestones
    Number of subjects started
    81
    Number of subjects completed
    81

    Period 1
    Period 1 title
    Treatment/Observation Period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    S-588410 group
    Arm description
    HLA-A*24:02 Positive receiving S-588410
    Arm type
    Experimental

    Investigational medicinal product name
    S-588410
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Emulsion for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients subcutaneously received 1 mL of S-588410 emulsion (1 mg of each peptide), once weekly for 12 weeks and once every 2 weeks thereafter for up to 24 months.

    Arm title
    Observation group
    Arm description
    HLA-A*24:02 Negative not receiving S-588410
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    S-588410 group Observation group
    Started
    45
    36
    Completed
    8
    4
    Not completed
    37
    32
         Aggravation of target disease
    33
    29
         Adverse event, non-fatal
    2
    -
         Consent withdrawn by subject
    2
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    S-588410 group
    Reporting group description
    HLA-A*24:02 Positive receiving S-588410

    Reporting group title
    Observation group
    Reporting group description
    HLA-A*24:02 Negative not receiving S-588410

    Reporting group values
    S-588410 group Observation group Total
    Number of subjects
    45 36 81
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    22 9 31
        From 65-84 years
    21 27 48
        85 years and over
    2 0 2
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    66.7 ± 9.0 67.4 ± 9.3 -
    Gender categorical
    Units: Subjects
        Female
    9 10 19
        Male
    36 26 62

    End points

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    End points reporting groups
    Reporting group title
    S-588410 group
    Reporting group description
    HLA-A*24:02 Positive receiving S-588410

    Reporting group title
    Observation group
    Reporting group description
    HLA-A*24:02 Negative not receiving S-588410

    Primary: CTL induction

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    End point title
    CTL induction
    End point description
    CTL induction in HLA-A*24-02-positive patients receiving S-588410 for 12 weeks
    End point type
    Primary
    End point timeframe
    12 weeks
    End point values
    S-588410 group Observation group
    Number of subjects analysed
    45
    36 [1]
    Units: patients
    42
    0
    Notes
    [1] - CTL induction in the observation group was not evaluated
    Statistical analysis title
    Primary analysis
    Statistical analysis description
    One-sided binomial test where the null hypothesis was that the CTL induction rate within 12 weeks was equal to 0.5 or less was performed at a significance level of 0.05.
    Comparison groups
    S-588410 group v Observation group
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    ≤ 0.05 [2]
    Method
    one-sided binomial test
    Parameter type
    Clopper-Pearson
    Point estimate
    93.3
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    83.7
         upper limit
    98.2
    Notes
    [2] - P-value is determined by one-sided binomial test where the null hypothesis that the CTL induction is equal to 0.5 or less

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from screening (up to 28 days before dosing) up to the end of treatment period (104 weeks) or discontinuation.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Treatment Group
    Reporting group description
    HLA-A*24:02 Positive receiving S-588410

    Reporting group title
    Observation Group
    Reporting group description
    HLA-A*24:02 Negative not receiving S-588410

    Serious adverse events
    Treatment Group Observation Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 45 (13.33%)
    5 / 36 (13.89%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    1
    0
    Cardiac disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 45 (0.00%)
    2 / 36 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Gait disturbance
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ileus
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal bacterial overgrowth
    Additional description: Small intestinal bacterial overgrowth
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periodontal disease
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Pyelonephritis
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Treatment Group Observation Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    44 / 45 (97.78%)
    21 / 36 (58.33%)
    Cardiac disorders
    Hypertension
         subjects affected / exposed
    3 / 45 (6.67%)
    2 / 36 (5.56%)
         occurrences all number
    3
    2
    Deep vein thrombosis
         subjects affected / exposed
    0 / 45 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Blood and lymphatic system disorders
    Haematuria
         subjects affected / exposed
    2 / 45 (4.44%)
    2 / 36 (5.56%)
         occurrences all number
    2
    3
    Respiratory, thoracic and mediastinal disorders
    Nasopharyngitis
         subjects affected / exposed
    6 / 45 (13.33%)
    2 / 36 (5.56%)
         occurrences all number
    12
    2
    Nervous system disorders
    Neuropathy peripheral
         subjects affected / exposed
    0 / 45 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    General disorders and administration site conditions
    Injection site reaction
         subjects affected / exposed
    42 / 45 (93.33%)
    0 / 36 (0.00%)
         occurrences all number
    47
    0
    Pyrexia
         subjects affected / exposed
    9 / 45 (20.00%)
    0 / 36 (0.00%)
         occurrences all number
    18
    0
    Headache
         subjects affected / exposed
    3 / 45 (6.67%)
    2 / 36 (5.56%)
         occurrences all number
    4
    2
    Insomnia
         subjects affected / exposed
    3 / 45 (6.67%)
    1 / 36 (2.78%)
         occurrences all number
    3
    1
    Malaise
         subjects affected / exposed
    3 / 45 (6.67%)
    0 / 36 (0.00%)
         occurrences all number
    5
    0
    Fatigue
         subjects affected / exposed
    1 / 45 (2.22%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    3 / 45 (6.67%)
    3 / 36 (8.33%)
         occurrences all number
    5
    3
    Constipation
         subjects affected / exposed
    3 / 45 (6.67%)
    1 / 36 (2.78%)
         occurrences all number
    3
    2
    Nausea
         subjects affected / exposed
    3 / 45 (6.67%)
    0 / 36 (0.00%)
         occurrences all number
    5
    0
    Abdominal pain
         subjects affected / exposed
    0 / 45 (0.00%)
    4 / 36 (11.11%)
         occurrences all number
    0
    5
    Gingivitis
         subjects affected / exposed
    0 / 45 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Dental caries
         subjects affected / exposed
    0 / 45 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Dyspepsia
         subjects affected / exposed
    0 / 45 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    2 / 45 (4.44%)
    2 / 36 (5.56%)
         occurrences all number
    2
    2
    Urinary tract infection
         subjects affected / exposed
    0 / 45 (0.00%)
    4 / 36 (11.11%)
         occurrences all number
    0
    5
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    4 / 45 (8.89%)
    0 / 36 (0.00%)
         occurrences all number
    5
    0
    Dermatitis contact
         subjects affected / exposed
    3 / 45 (6.67%)
    0 / 36 (0.00%)
         occurrences all number
    3
    0
    Pruritus
         subjects affected / exposed
    3 / 45 (6.67%)
    0 / 36 (0.00%)
         occurrences all number
    3
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 45 (2.22%)
    4 / 36 (11.11%)
         occurrences all number
    1
    4
    Pain in extremity
         subjects affected / exposed
    1 / 45 (2.22%)
    2 / 36 (5.56%)
         occurrences all number
    1
    3
    Musculoskeletal pain
         subjects affected / exposed
    0 / 45 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    0
    4
    Infections and infestations
    Helicobacter infection
         subjects affected / exposed
    0 / 45 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Mar 2015
    - Inclusion of the expansion of the term bladder cancer. - Update of the inclusion and exclusion criteria.

    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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