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    Clinical Trial Results:
    OPTIMAL - Titration of treatment with biologics in severe asthma

    Summary
    EudraCT number
    		 2020-003358-63
    Trial protocol
    		 DK  
    Global end of trial date
    28 Sep 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Jan 2024
    First version publication date
    28 Jan 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    2020033183.
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04648761
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bispebjerg Hospital
    Sponsor organisation address
    Ebba Lunds Vej 48, Copenhagen NV, Denmark, 2400
    Public contact
    Lungemedicinsk Forskningsenhed, Bispebjerg Hospital, +45 38635122,
    Scientific contact
    Lungemedicinsk Forskningsenhed, Bispebjerg Hospital, +45 38635122,
    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
    27 Sep 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Sep 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Sep 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of the OPTIMAL study is to is to examine the OPTIMAL algorithm as a clinical tool for safe dose titration of biologics in patients with severe asthma. We will investigate if treatment with biologics can be stepped down or even terminated in some patients without loss of disease control. We will investigate possible predictors of successful dose tapering in order to identify patients who are can have their dosage tapered and those who cannot. The OPTIMAL study will also describe potential adverse effects of stepping down or discontinuing treatment. The OPTIMAL study will focus on biologics with an anti-IL5/IL5r effect. We will also describe immunological changes during dosetitration.
    Protection of trial subjects
    All patients were on high dose ICS during the trial
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Jan 2021
    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: 73
    Worldwide total number of subjects
    73
    EEA total number of subjects
    73
    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)
    46
    From 65 to 84 years
    27
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruited from respiratory outpatient clinical at the five participating centers in Denmark

    Pre-assignment
    Screening details
    		 Patient eligable for the trial were on an anti-IL5 biologic (mepolizumab, benralizumab or reslizumab) and had been free from exacerbations of oral corticosteroid use in the 12 moths before inclusion.

    Period 1
    Period 1 title
    January 13th 2021 - September 27th 2023 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    The study was open-label

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Control arm
    Arm description
    		 Patients randomised to continue biological treatment withput intervention
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Active arm
    Arm description
    		 Randomised to have intervals between biological treatment adjusted by the OPTIMAL titration algorithm
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mepolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for dispersion for injection
    Routes of administration
    Injection
    Dosage and administration details
    To be adjusted via the OPTIMAL titration algorithm

    Investigational medicinal product name
    Benralizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for dispersion for injection
    Routes of administration
    Injection
    Dosage and administration details
    Ti be adjusted via the OPTIMAL titration algorithm

    Number of subjects in period 1
    		Control arm Active arm
    Started
    36
    37
    Completed
    35
    37
    Not completed
    1
    0
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Control arm
    Reporting group description
    		 Patients randomised to continue biological treatment withput intervention

    Reporting group title
    Active arm
    Reporting group description
    		 Randomised to have intervals between biological treatment adjusted by the OPTIMAL titration algorithm

    Reporting group values
    		 Control arm Active arm Total
    Number of subjects
    		 36 37 73
    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
    Age
    Units: years
        arithmetic mean (standard deviation)
    		 59 ( 13 ) 61 ( 10 ) -
    Gender categorical
    Units: Subjects
        Female
    		 15 13 28
        Male
    		 21 24 45
    Subject analysis sets

    Subject analysis set title
    Control arm
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patient who completed the study

    Subject analysis sets values
    		 Control arm
    Number of subjects
    35
    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)
        From 65-84 years
        85 years and over
    Age continuous
    Age
    Units: years
        arithmetic mean (standard deviation)
    59 ( 13 )
    Gender categorical
    Units: Subjects
        Female
    15
        Male
    20

    End points

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    End points reporting groups
    Reporting group title
    Control arm
    Reporting group description
    		 Patients randomised to continue biological treatment withput intervention

    Reporting group title
    Active arm
    Reporting group description
    		 Randomised to have intervals between biological treatment adjusted by the OPTIMAL titration algorithm

    Subject analysis set title
    Control arm
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patient who completed the study

    Primary: Proportion of patients with an exacerbation

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    End point title
    		 Proportion of patients with an exacerbation [1]
    End point description
    End point type
    Primary
    End point timeframe
    During the one year follow-up
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: I have only reported for the patients who hjave completed the study i.e. the all patient in the active arm and the sub group (35 of 36) in the control arm.
    End point values
    		 Active arm Control arm
    Number of subjects analysed
    37
    35
    Units: Percent
    32
    17
    Statistical analysis title
    		 Chi squared test
    Comparison groups
    Active arm v Control arm
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.13
    Method
    		 Chi-squared
    Parameter type
    		 Proportion
    Confidence interval

    Secondary: Ability to titrate in active arm

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    End point title
    		 Ability to titrate in active arm [2]
    End point description
    End point type
    Secondary
    End point timeframe
    At the end of the trial
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only relevant in the active arm.
    End point values
    		 Active arm
    Number of subjects analysed
    37
    Units: Percent
        Uanble to titrate
    22
        Interval increase of 50 %
    18
        Interval increase of 125 %
    38
        Cessation of treatment
    22
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    January 13th 2021 to September 27th 2023
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    1
    Reporting groups
    Reporting group title
    All patients
    Reporting group description
    		 -

    Serious adverse events
    		 All patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 72 (8.33%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Mesothelioma malignant
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Aortic valve stenosis
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Cervical spinal stenosis
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Borrelia infection
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 All patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 72 (22.22%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences all number
    1
    General disorders and administration site conditions
    Nephrolithiasis
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    International normalised ratio increased
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences all number
    1
    Epistaxis
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences all number
    1
    Endocrine disorders
    Hypokalaemia
         subjects affected / exposed
    2 / 72 (2.78%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Trigger finger
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences all number
    1
    Pain in extremity
         subjects affected / exposed
    2 / 72 (2.78%)
         occurrences all number
    2
    Cramp-fasciculation syndrome
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences all number
    1
    Fracture
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences all number
    1
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences all number
    1
    Oral candidiasis
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences all number
    1
    Pneumonia
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences all number
    1
    Rhinitis
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences all number
    1
    Malaise
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Nov 2022
    Reduction of requried participant from 150 to 74

    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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