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    Clinical Trial Results:
    PONENTE: A Multicenter, Open-label, Phase 3b Efficacy and Safety Study of Benralizumab 30 mg Administered Subcutaneously to Reduce Oral Corticosteroid Use in Adult Patients with Severe Eosinophilic Asthma on High-Dose Inhaled Corticosteroid plus Long-acting β2 Agonist and Chronic Oral Corticosteroid Therapy

    Summary
    EudraCT number
    		 2018-000170-30
    Trial protocol
    		 DE   DK   SE   ES   PL   BE   GB   IT  
    Global end of trial date
    24 Mar 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Mar 2023
    First version publication date
    31 Mar 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D3250C00065
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03557307
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    S-151, Sodertalje, Sweden,
    Public contact
    AstraZeneca Information Center, AstraZeneca, +1 8002369933, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca, +1 8772409479, information.center@astrazeneca.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
    13 Sep 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Mar 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the ability to reduce OCS dose in adult patients with severe eosinophilic asthma treated with benralizumab 30 mg SC
    Protection of trial subjects
    This study is conducted in accordance with the protocol and with the following: Consensus ethical principles derived from international guidelines including the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines; Applicable International Conference on Harmonisation (ICH)/Good Clinical Practice (GCP) Guidelines; Applicable laws and regulations. The protocol, protocol amendments, Informed Consent Form (ICF), Investigator Brochure, and other relevant documents (e.g. advertisements) must be submitted to an Institutional Review Board/Independent Ethics Committee (IRB/IEC) by the Investigator and reviewed and approved by the IRB/IEC before the study is initiated. Any amendments to the protocol will require IRB/IEC approval before implementation of changes made to the study design, except for changes necessary to eliminate an immediate hazard to study patients. Where applicable as per relevant laws and regulations, amendments will also be submitted to, reviewed and approved by regulatory authorities/national competent authorities.
    Background therapy
    		 If a patient was using an alternative oral corticosteroids (OCS) product other than prednisone/prednisolone prior to visit 1, the Investigator would switch to prednisone/prednisolone at visit 1. A stable dose of OCS must have been maintained for ≥4 weeks prior to Visit 1.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Aug 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Scientific research
    Long term follow-up duration
    		 12 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 68
    Country: Number of subjects enrolled
    Belgium: 12
    Country: Number of subjects enrolled
    Brazil: 20
    Country: Number of subjects enrolled
    Canada: 17
    Country: Number of subjects enrolled
    Colombia: 27
    Country: Number of subjects enrolled
    Denmark: 21
    Country: Number of subjects enrolled
    France: 10
    Country: Number of subjects enrolled
    Germany: 39
    Country: Number of subjects enrolled
    Italy: 35
    Country: Number of subjects enrolled
    Mexico: 63
    Country: Number of subjects enrolled
    Poland: 60
    Country: Number of subjects enrolled
    Russian Federation: 60
    Country: Number of subjects enrolled
    Spain: 47
    Country: Number of subjects enrolled
    Sweden: 5
    Country: Number of subjects enrolled
    Taiwan: 22
    Country: Number of subjects enrolled
    United Kingdom: 30
    Country: Number of subjects enrolled
    United States: 62
    Worldwide total number of subjects
    598
    EEA total number of subjects
    229
    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)
    465
    From 65 to 84 years
    133
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Of the 705 patients who provided informed consent and were screened, 598 (84.8%) were eligible to receive Benralizumab 30 mg and entered the study. All 598 (100%) patients received the study drug. 195 of the 538 patients who completed the main study treatment enrolled into PONENTE Long Term Follow Up Substudy.

    Pre-assignment
    Screening details
    		 At the first visit, patients were evaluated regarding inclusion and exclusion criteria. Then only those eligible to receive Benra 30 mg were assigned treatment and entered a 4-week induction phase on a stable dose of oral corticosteroids. In Substudy, patients were treated according to healthcare provider discretion with no IP provided by sponsor.

    Period 1
    Period 1 title
    To End of OCS reduction phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Benra 30 mg
    Arm description
    		 Benralizumab 30 mg administered subcutaneously every 4 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Benralizumab
    Investigational medicinal product code
    Other name
    Fasenra
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Benralizumab 30 mg administered subcutaneously every 4 weeks

    Number of subjects in period 1
    		Benra 30 mg
    Started
    598
    Completed
    563
    Not completed
    35
         Adverse event, serious fatal
    2
         Consent withdrawn by subject
    10
         Failure to meet inclusion/exclusion criteria
    2
         Adverse event, non-fatal
    7
         other
    3
         Lost to follow-up
    5
         Protocol deviation
    6
    Period 2
    Period 2 title
    Maintenance phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Benra 30 mg
    Arm description
    		 Benralizumab 30 mg administered subcutaneously every 4 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Benralizumab
    Investigational medicinal product code
    Other name
    Fasenra
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Benralizumab 30 mg administered subcutaneously every 4 weeks

    Number of subjects in period 2
    		Benra 30 mg
    Started
    563
    Completed
    536
    Not completed
    27
         Adverse event, serious fatal
    3
         Consent withdrawn by subject
    2
         Adverse event, non-fatal
    4
         Pregnancy
    2
         other
    3
         Lost to follow-up
    2
         Protocol deviation
    11
    Period 3
    Period 3 title
    Long term follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Asthma treatment as per healthcare provider discretion
    Arm description
    		 Treated as per healthcare provider's discretion. IP or medications were not provided by the sponsor.
    Arm type
    		 treated as per healthcare provider's discretion

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 3 [1]
    		Asthma treatment as per healthcare provider discretion
    Started
    195
    Completed
    195
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Of the 536 patients who completed main study maintenance phase, only 195 consented and enrolled to the long term follow up substudy.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Benra 30 mg
    Reporting group description
    		 Benralizumab 30 mg administered subcutaneously every 4 weeks

    Reporting group values
    		 Benra 30 mg Total
    Number of subjects
    		 598 598
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 465 465
        From 65-84 years
    		 133 133
        85 years and over
    		 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53.3 ( 13.59 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 383 383
        Male
    		 215 215
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 475 475
        Black or African American
    		 26 26
        Asian
    		 29 29
        Native Hawaiian or other Pacific Islander
    		 1 1
        American Indian or Alaska Native
    		 46 46
        Other
    		 12 12
        unknown
    		 9 9
    Subject analysis sets

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All enrolled patients who received at least one dose of benralizumab are included in the FAS, irrespective of their protocol adherence and continued participation in the study.

    Subject analysis set title
    Long term follow-up analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients who enrolled in Long Term Follow Up substudy

    Subject analysis set title
    Biologic analysis set
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients who have >=50% exposure to any biologic treatment for asthma from the end of maintenance phase of the main study to the Long Term Follow Up visit

    Subject analysis set title
    Benra analysis set
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients who have >=50% exposure to benralizumab from the end of maintenance phase of the main study to the Long Term follow Up visit, and no previous or concurrent exposure to any other biologic during this period

    Subject analysis sets values
    		 Full analysis set Long term follow-up analysis set Biologic analysis set Benra analysis set
    Number of subjects
    598
    195
    78
    69
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
    465
    166
    66
    59
        From 65-84 years
    133
    29
    12
    10
        85 years and over
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    53.3 ( 13.59 )
    51.9 ( 12.7 )
    52.4 ( 12.2 )
    52.5 ( 11.69 )
    Sex: Female, Male
    Units: participants
        Female
    383
    115
    47
    40
        Male
    215
    80
    31
    29
    Race/Ethnicity, Customized
    Units: Subjects
        White
    475
    151
    64
    58
        Black or African American
    26
    8
    2
    1
        Asian
    29
    6
    3
    2
        Native Hawaiian or other Pacific Islander
    1
    0
    0
    0
        American Indian or Alaska Native
    46
    22
    5
    5
        Other
    12
    5
    1
    1
        unknown
    9
    3
    3
    2

    End points

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    End points reporting groups
    Reporting group title
    Benra 30 mg
    Reporting group description
    		 Benralizumab 30 mg administered subcutaneously every 4 weeks
    Reporting group title
    Benra 30 mg
    Reporting group description
    		 Benralizumab 30 mg administered subcutaneously every 4 weeks
    Reporting group title
    Asthma treatment as per healthcare provider discretion
    Reporting group description
    		 Treated as per healthcare provider's discretion. IP or medications were not provided by the sponsor.

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All enrolled patients who received at least one dose of benralizumab are included in the FAS, irrespective of their protocol adherence and continued participation in the study.

    Subject analysis set title
    Long term follow-up analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients who enrolled in Long Term Follow Up substudy

    Subject analysis set title
    Biologic analysis set
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients who have >=50% exposure to any biologic treatment for asthma from the end of maintenance phase of the main study to the Long Term Follow Up visit

    Subject analysis set title
    Benra analysis set
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients who have >=50% exposure to benralizumab from the end of maintenance phase of the main study to the Long Term follow Up visit, and no previous or concurrent exposure to any other biologic during this period

    Primary: Patients who achieve 100% reduction in daily OCS dose

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    End point title
    		 Patients who achieve 100% reduction in daily OCS dose [1]
    End point description
    Patients who achieve 100% reduction in daily OCS dose that are sustained over at least 4 weeks without worsening of asthma
    End point type
    Primary
    End point timeframe
    Baseline to end of OCS reduction phase, an average of approximately 200 days (The duration of the OCS reduction phase may vary based on asthma exacerbations, asthma worsening, HPA integrity , or other safety issues altering the OCS titration schedule.)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This is a single arm study and no comparison between arms is planned.
    End point values
    		 Benra 30 mg Full analysis set
    Number of subjects analysed
    598
    598
    Units: participants
    376
    376
    No statistical analyses for this end point

    Primary: Patients who achieve 100% reduction or a daily OCS dose of <=5mg

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    End point title
    		 Patients who achieve 100% reduction or a daily OCS dose of <=5mg [2]
    End point description
    Patients who achieve 100% reduction or a daily OCS dose of <=5mg, if reason for no further OCS reduction is Adrenal Insufficiency, that are sustained over at least 4 weeks without worsening of asthma
    End point type
    Primary
    End point timeframe
    Baseline to end of OCS reduction phase, an average of approximately 200 days (The duration of the OCS reduction phase may vary based on asthma exacerbations, asthma worsening, HPA integrity , or other safety issues altering the OCS titration schedule.)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This is a single arm study and no comparison between arms is planned.
    End point values
    		 Benra 30 mg Full analysis set
    Number of subjects analysed
    598
    598
    Units: participants
    490
    490
    No statistical analyses for this end point

    Secondary: Patients who achieve a ≥90%, ≥75%, and ≥50% reduction in daily OCS dose

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    End point title
    		 Patients who achieve a ≥90%, ≥75%, and ≥50% reduction in daily OCS dose
    End point description
    Patients who achieve a ≥90%, ≥75%, and ≥50% reduction in daily OCS dose that are sustained over at least 4 weeks without worsening of asthma
    End point type
    Secondary
    End point timeframe
    Baseline to end of OCS reduction phase, an average of approximately 200 days (The duration of the OCS reduction phase may vary based on asthma exacerbations, asthma worsening, HPA integrity , or other safety issues altering the OCS titration schedule.)
    End point values
    		 Benra 30 mg Full analysis set
    Number of subjects analysed
    598
    598
    Units: participants
        ≥90% reduction
    383
    383
        ≥75% reduction
    412
    412
        ≥50% reduction
    489
    489
    No statistical analyses for this end point

    Secondary: Change from baseline in average daily OCS dose (mg)

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    End point title
    		 Change from baseline in average daily OCS dose (mg)
    End point description
    Change from baseline in average daily OCS dose (mg) from start of OCS reduction to end of the OCS reduction phase
    End point type
    Secondary
    End point timeframe
    Baseline to end of OCS reduction phase, an average of approximately 200 days (The duration of the OCS reduction phase may vary based on asthma exacerbations, asthma worsening, HPA integrity , or other safety issues altering the OCS titration schedule.)
    End point values
    		 Benra 30 mg Full analysis set
    Number of subjects analysed
    593
    593
    Units: mg
        arithmetic mean (confidence interval 95%)
    -8.50 (-9.10 to -7.90)
    -8.50 (-9.10 to -7.90)
    No statistical analyses for this end point

    Secondary: Patients who achieve a daily OCS of ≤5mg

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    End point title
    		 Patients who achieve a daily OCS of ≤5mg
    End point description
    Patients who achieve a daily OCS dose of ≤5 mg (regardless of reason for no further OCS reduction), that are sustained over at least 4 weeks without worsening of asthma
    End point type
    Secondary
    End point timeframe
    Baseline to end of OCS reduction phase, an average of approximately 200 days (The duration of the OCS reduction phase may vary based on asthma exacerbations, asthma worsening, HPA integrity , or other safety issues altering the OCS titration schedule.)
    End point values
    		 Benra 30 mg Full analysis set
    Number of subjects analysed
    598
    598
    Units: participants
    547
    547
    No statistical analyses for this end point

    Other pre-specified: Patients who achieve 100% reduction in daily OCS dose from main study baseline OCS dose to the end of the long term follow up substudy

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    End point title
    		 Patients who achieve 100% reduction in daily OCS dose from main study baseline OCS dose to the end of the long term follow up substudy
    End point description
    Patients who achieve 100% reduction in daily OCS dose that are sustained over at least 4 weeks without worsening of asthma
    End point type
    Other pre-specified
    End point timeframe
    from main study baseline to the end of the long term follow up substudy, an average of approximate 922 days.
    End point values
    		 Asthma treatment as per healthcare provider discretion Long term follow-up analysis set Biologic analysis set Benra analysis set
    Number of subjects analysed
    195
    195
    78
    69
    Units: participants
    138
    138
    60
    54
    No statistical analyses for this end point

    Other pre-specified: Patients who achieve a daily OCS dose of ≤5 mg at the end of the long term follow up substudy

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    End point title
    		 Patients who achieve a daily OCS dose of ≤5 mg at the end of the long term follow up substudy
    End point description
    Patients who achieve a daily OCS dose of ≤5 mg (regardless of reason for no further OCS reduction), that are sustained over at least 4 weeks without worsening of asthma
    End point type
    Other pre-specified
    End point timeframe
    from main study baseline to the end of the long term follow up substudy, an average of approximate 922 days.
    End point values
    		 Asthma treatment as per healthcare provider discretion Long term follow-up analysis set Biologic analysis set Benra analysis set
    Number of subjects analysed
    195
    195
    78
    69
    Units: participants
    177
    177
    72
    65
    No statistical analyses for this end point

    Other pre-specified: Patients who achieve ≥90%, ≥75%, ≥50% or >0% OCS reduction from main study baseline OCS dose to the end of the long term follow up substudy

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    End point title
    		 Patients who achieve ≥90%, ≥75%, ≥50% or >0% OCS reduction from main study baseline OCS dose to the end of the long term follow up substudy
    End point description
    Patients who achieve a ≥90%, ≥75%, and ≥50% reduction in daily OCS dose that are sustained over at least 4 weeks without worsening of asthma
    End point type
    Other pre-specified
    End point timeframe
    from main study baseline to the end of the long term follow up substudy, an average of approximate 922 days.
    End point values
    		 Asthma treatment as per healthcare provider discretion Long term follow-up analysis set Biologic analysis set Benra analysis set
    Number of subjects analysed
    195
    195
    78
    69
    Units: participants
        >=90% reduction
    141
    141
    61
    55
        >=75% reduction
    151
    151
    64
    58
        >=50% reduction
    172
    172
    71
    64
        >0% reduction
    175
    175
    72
    65
    No statistical analyses for this end point

    Other pre-specified: Change in daily OCS dose (mg) from main study baseline to the end of the long term follow up substudy

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    End point title
    		 Change in daily OCS dose (mg) from main study baseline to the end of the long term follow up substudy
    End point description
    Change in average daily OCS dose (mg) from main study baseline to the end of the long term follow up substudy
    End point type
    Other pre-specified
    End point timeframe
    from main study baseline to the end of the long term follow up substudy, an average of approximate 922 days.
    End point values
    		 Asthma treatment as per healthcare provider discretion Long term follow-up analysis set Biologic analysis set Benra analysis set
    Number of subjects analysed
    195
    195
    78
    69
    Units: mg
        arithmetic mean (confidence interval 95%)
    -10.01 (-11.26 to -8.76)
    -10.01 (-11.26 to -8.76)
    -10.28 (-12.16 to -8.41)
    -10.8 (-12.85 to -8.75)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Main study: From first dose of study drug until end of study, with an average of 405 days. Substudy: on-study period, between the date of informed consent for the substudy and the last available visit or contact for a patient, with an average of 18 days.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Benra 30 mg
    Reporting group description
    		 Benralizumab 30 mg administered subcutaneously every 4 weeks

    Reporting group title
    Asthma treatment as per healthcare provider discretion
    Reporting group description
    		 Treated as per healthcare provider's discretion. IP or medications were not provided by the sponsor.

    Serious adverse events
    		 Benra 30 mg Asthma treatment as per healthcare provider discretion
    Total subjects affected by serious adverse events
         subjects affected / exposed
    89 / 598 (14.88%)
    0 / 195 (0.00%)
         number of deaths (all causes)
    5
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neurofibroma
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant glioma
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Embolism arterial
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive emergency
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Sudden cardiac death
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Reproductive system and breast disorders
    Breast calcifications
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pharyngeal swelling
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspirin-exacerbated respiratory disease
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    23 / 598 (3.85%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 33
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic rhinosinusitis with nasal polyps
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Oxygen saturation decreased
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Alcohol poisoning
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    2 / 598 (0.33%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    4 / 598 (0.67%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    2 / 598 (0.33%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (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
    Apallic syndrome
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery aneurysm
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness postural
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Meniere's disease
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis acute
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    2 / 598 (0.33%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polymyalgia rheumatica
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    2 / 598 (0.33%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    2 / 598 (0.33%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemophilus infection
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected bite
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    5 / 598 (0.84%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic abscess
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    11 / 598 (1.84%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    2 / 598 (0.33%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia haemophilus
         subjects affected / exposed
    2 / 598 (0.33%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection bacterial
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 598 (0.50%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Benra 30 mg Asthma treatment as per healthcare provider discretion
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    181 / 598 (30.27%)
    0 / 195 (0.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    21 / 598 (3.51%)
    0 / 195 (0.00%)
         occurrences all number
    21
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    29 / 598 (4.85%)
    0 / 195 (0.00%)
         occurrences all number
    38
    0
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    33 / 598 (5.52%)
    0 / 195 (0.00%)
         occurrences all number
    34
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    64 / 598 (10.70%)
    0 / 195 (0.00%)
         occurrences all number
    92
    0
    Sinusitis
         subjects affected / exposed
    19 / 598 (3.18%)
    0 / 195 (0.00%)
         occurrences all number
    22
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    28 / 598 (4.68%)
    0 / 195 (0.00%)
         occurrences all number
    31
    0
    Upper respiratory tract infection
         subjects affected / exposed
    25 / 598 (4.18%)
    0 / 195 (0.00%)
         occurrences all number
    28
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Jan 2019
    Clarified study design, objectives, statistical methods, inclusion/exclusion criteria and Study Plan and Timing of procedures.
    06 Nov 2019
    The cortisol test pathway has been strengthened. All reference to the sputum substudy has been deleted. The sub-study was terminated due to low enrollment rate. Sputum samples already collected at the time of this amendment will not be analyzed, and will be destroyed.
    17 Oct 2020
    This amendment includes the addition of a long-term follow-up visit 12 to 18 months after end of PONENTE treatment period where we will retrospectively collect data to understand changes in OCS dose and other background asthma therapy, and occurrence of asthma exacerbations under real-world conditions. We will also evaluate the recovery from adrenal insufficiency (AI) and the long-term impact of OCS reduction achieved during PONENTE study on the glucocorticoid toxicity.

    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.
    During COVID-19 pandemic, for ongoing patients, patient dosing, and scheduled visits are inevitably impacted, but the primary endpoint was not impacted.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/34619104
    http://www.ncbi.nlm.nih.gov/pubmed/31579676
    http://www.ncbi.nlm.nih.gov/pubmed/35896216
    http://www.ncbi.nlm.nih.gov/pubmed/36769635
    http://www.ncbi.nlm.nih.gov/pubmed/35246123
    For support, Contact us.
    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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