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    Clinical Trial Results:
    SIGNATURE - the 6-gene signature as a predictor of response to treatment in severe asthma and ACOS

    Summary
    EudraCT number
    		 2017-000495-28
    Trial protocol
    		 DK  
    Global end of trial date
    30 Jun 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Jan 2021
    First version publication date
    06 Jan 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    132
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Respiratory Research Unit
    Sponsor organisation address
    Ebba Lunds Vej 48, Copenhagen NV, Denmark, 2400
    Public contact
    Celeste Porsbjerg, Respiratory Research Unit, Bispebjerg University Hospital, laurits.froessing@regionh.dk
    Scientific contact
    Celeste Porsbjerg, Respiratory Research Unit, Bispebjerg University Hospital, laurits.froessing@regionh.dk
    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
    30 Nov 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Jun 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jun 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial is to develop a tool able to predict response to oral corticosteroids in patients with severe asthma or ACOS using the 6-gene signature.
    Protection of trial subjects
    Patients were thoroughly informed of the side effects of the intervention (oral corticosteroids) and were encouraged to contact the study team if any symptoms arose.
    Background therapy
    		 All patients received maintenance therapy for asthma included but not limited to inhaled corticosteroids and long acting beta2 agonists.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Mar 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 81
    Worldwide total number of subjects
    81
    EEA total number of subjects
    81
    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)
    60
    From 65 to 84 years
    21
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited from the outpatient clinic at Bispebjerg University Hospital, Denmark.

    Pre-assignment
    Screening details
    		 This study had no run-in og screening period. Patients attending the respiratory outpatient clinic at Bispebjerg University Hospital were screened for eligibility by asking them about * their maintenance asthma treatment * recent exacerbations or airway infections

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

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

    Arms
    Arm title
    		 Follow-up
    Arm description
    		 Single-arm Prednisolone 37.5 mg once daily for 14 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    Prednisolon DAK
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    37.5 mg once daily for 14 days Administered as 1.5 tbl of 25mg.

    Number of subjects in period 1
    		Follow-up
    Started
    81
    Completed
    75
    Not completed
    6
         Consent withdrawn by subject
    5
         Adverse event, non-fatal
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall
    Reporting group description
    		 -

    Reporting group values
    		 Overall Total
    Number of subjects
    		 81 81
    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)
    		 55.6 ± 11.0 -
    Gender categorical
    Units: Subjects
        Female
    		 38 38
        Male
    		 43 43

    End points

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    End points reporting groups
    Reporting group title
    Follow-up
    Reporting group description
    		 Single-arm Prednisolone 37.5 mg once daily for 14 days

    Subject analysis set title
    Severe asthma only
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Analysis of patients with severe asthma only

    Subject analysis set title
    Baseline population
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Work-around as one-arm study

    Primary: Clinical improvement. Composite end point

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    End point title
    		 Clinical improvement. Composite end point
    End point description
    Clinical response to OCS was defined using current ATS/ERS criteria(9–12): a significant change in lung function (increase in FEV1 by ≥12% and ≥200 mL (10); and/or a decrease in FeNO of 20% if baseline FeNO ≥50 ppb or a decrease of ≥10 ppb if FeNO < 50 ppb at baseline(11); and/or a change in asthma control (decrease in ACQ5 of ≥0.5) (12).
    End point type
    Primary
    End point timeframe
    from baseline to end of study
    End point values
    		 Follow-up Severe asthma only Baseline population
    Number of subjects analysed
    25
    25
    25
    Units: number
    number (not applicable)
        Improvement
    4
    4
    4
        No improvement
    21
    21
    21
    Attachments
    		 Flow chart of included patients in composite EP
    Statistical analysis title
    		 Logistic regression, gene expression
    Statistical analysis description
    A clinical response to OCS was observed in 68% of patients(n=25): 4% had a significant increase in FEV1, 36% had a significant decrease in FeNO, and 44% had a significant improvement in ACQ5. Response to OCS was significantly predicted using both a combination of T2 biomarkers (FeNO, B-EOS and sputum eosinophil count; AUC 0.82, p=0.03) and expression of all T2 genes combined ( AUC 0.95, p=0.002). Further, OCS response was significantly predicted by the IL-5-related genes a
    Comparison groups
    Follow-up v Baseline population v Severe asthma only
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.002
    Method
    		 Regression, Logistic
    Parameter type
    		 AUC
    Confidence interval
    Notes
    [1] - Prediction of a favourable composite outcome was predicted using gene expression using the 6-gene signature which is a composite biomarker, consisting of 3 eosinophilic- (CLC, CPA3, DNASE1L3) and 3 neutrophilic genes (IL1B, ALPL and CXCR2) and the genes constituting the signature were chosen based on their ability to predict sputum eosinophilia and sputum neutrophilia, respectively.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From inrollment in the study to end of study. No extended observation period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    Intervention
    Reporting group description
    		 Prednisolone 37.5 mg once daily for 14 days

    Serious adverse events
    		 Intervention
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 81 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Intervention
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 81 (17.28%)
    Gastrointestinal disorders
    Increased reflux
         subjects affected / exposed
    3 / 81 (3.70%)
         occurrences all number
    3
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    10 / 81 (12.35%)
         occurrences all number
    10
    Infections and infestations
    Oral candidiasis
         subjects affected / exposed
    2 / 81 (2.47%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    This study has only been analysed for the prespecified severe-asthma only sub-population.
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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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