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    Clinical Trial Results:
    A Phase IIa, Multicenter, Randomized, Placebo-Controlled, Double-Blind Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of MTPS9579A in Patients With Asthma Requiring Inhaled Corticosteroids and a Second Controller.

    Summary
    EudraCT number
    		 2019-000795-41
    Trial protocol
    		 PL   DE  
    Global end of trial date
    19 May 2022

    Results information
    Results version number
    		 v2(current)
    This version publication date
    03 Sep 2023
    First version publication date
    27 May 2023
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Changes in the screening details and outcome measure section.

    Trial information

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    Trial identification
    Sponsor protocol code
    GB41149
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04092582
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Hoffmann-La Roche
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    Medical Communications, F. Hoffmann-La Roche AG, + 41 616878333, global.trial_information@roche.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
    19 May 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 May 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study was to evaluate the efficacy, safety, and pharmacokinetics of MTPS9579A compared with placebo in participants with uncontrolled asthma despite the use of inhaled corticosteroids (ICS) and a second controller.
    Protection of trial subjects
    The study was conducted in full conformance with the ICH E6 guideline for Good Clinical Practice and the principles of the Declaration of Helsinki, or the laws and regulations of the country in which the research is conducted, whichever affords the greater protection to the subject. All subjects were required to sign an informed consent form before enrolling in the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Oct 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 12
    Country: Number of subjects enrolled
    Peru: 6
    Country: Number of subjects enrolled
    United States: 33
    Country: Number of subjects enrolled
    Germany: 25
    Country: Number of subjects enrolled
    Poland: 58
    Worldwide total number of subjects
    134
    EEA total number of subjects
    83
    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)
    102
    From 65 to 84 years
    32
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in the study at 26 investigative sites in 5 countries (Argentina, Germany, Peru, Poland, and the United States) from 31 October 2019 to 19 May 2022.

    Pre-assignment
    Screening details
    		 This study included a 2-week single-blind placebo run-in period. A total of 135 participants were randomized in double-blind treatment period. Of the 135 participants randomized, 134 participants received at least one dose of study drug and their intended treatment.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Carer, Subject, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 MTPS9579A, 1800 mg
    Arm description
    		 Participants with uncontrolled moderate to severe asthma received Placebo, given as intravenous (IV) infusion, for 14 days in the Placebo run-in period. Participants then received MTPS9579A, 1800 mg, given as IV infusion at randomization (Week 2), Week 6, and every 4 weeks thereafter through Week 46.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MTPS9579A
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    MTPS9579A was administered as an IV Infusion at a dose of 1800 mg.

    Arm title
    		 Placebo
    Arm description
    		 Participants with uncontrolled moderate to severe asthma received Placebo, given as IV infusion, for 14 days in the Placebo run-in period. Participants received MTPS9579A matching placebo, given as IV infusion at randomization (Week 2), Week 6, and every 4 weeks thereafter through Week 46.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    MTPS9579A-matching placebo was administered as an IV Infusion.

    Number of subjects in period 1
    		MTPS9579A, 1800 mg Placebo
    Started
    69
    65
    Safety Population
    69
    65
    Completed
    64
    63
    Not completed
    5
    2
         Adverse event, serious fatal
    1
    1
         Consent withdrawn by subject
    4
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MTPS9579A, 1800 mg
    Reporting group description
    		 Participants with uncontrolled moderate to severe asthma received Placebo, given as intravenous (IV) infusion, for 14 days in the Placebo run-in period. Participants then received MTPS9579A, 1800 mg, given as IV infusion at randomization (Week 2), Week 6, and every 4 weeks thereafter through Week 46.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants with uncontrolled moderate to severe asthma received Placebo, given as IV infusion, for 14 days in the Placebo run-in period. Participants received MTPS9579A matching placebo, given as IV infusion at randomization (Week 2), Week 6, and every 4 weeks thereafter through Week 46.

    Reporting group values
    		 MTPS9579A, 1800 mg Placebo Total
    Number of subjects
    		 69 65 134
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 52 50 102
        From 65-84 years
    		 17 15 32
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54.7 ( 12.0 ) 52.9 ( 13.2 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 39 34 73
        Male
    		 30 31 61
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 3 0 3
        Asian
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 3 3
        White
    		 62 59 121
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 4 3 7
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 10 12 22
        Not Hispanic or Latino
    		 59 53 112
        Unknown or Not Reported
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    MTPS9579A, 1800 mg
    Reporting group description
    		 Participants with uncontrolled moderate to severe asthma received Placebo, given as intravenous (IV) infusion, for 14 days in the Placebo run-in period. Participants then received MTPS9579A, 1800 mg, given as IV infusion at randomization (Week 2), Week 6, and every 4 weeks thereafter through Week 46.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants with uncontrolled moderate to severe asthma received Placebo, given as IV infusion, for 14 days in the Placebo run-in period. Participants received MTPS9579A matching placebo, given as IV infusion at randomization (Week 2), Week 6, and every 4 weeks thereafter through Week 46.

    Primary: Time to First Composite Asthma Exacerbations (CompEX) Event

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    End point title
    		 Time to First Composite Asthma Exacerbations (CompEX) Event
    End point description
    CompEX=time from randomisation to first asthma exacerbation/diary worsening during treatment.Asthma exacerbation=new/increased asthma symptoms in one/both: Hospitalisation/emergency department visit with administration of systemic corticosteroid treatment (SC);Treatment with SC for atleast 3 days,/a long-acting depot corticosteroid preparation with therapeutic effectiveness of atleast 3 days.Diaryworsening=occurrence of prespecified changes:morning peak expiratory flow rate (PEFR),evening PEFR,morning symptom score,evening symptom score,morning short-acting rescue therapy use,&evening short-acting rescue therapy use.999=Data for median upper limit (UL) of confidence interval (CI) was not estimable due to insufficient number of participants with events.9999=Data for UL of CI was not estimable due to insufficient number of participants with events.Hazard ratio was used for analysis.mITT population included all randomised participants who received at least one dose of study treatment.
    End point type
    Primary
    End point timeframe
    Randomisation [Week 2] to end of treatment (EOT) [Week 50]
    End point values
    		 MTPS9579A, 1800 mg Placebo
    Number of subjects analysed
    69
    65
    Units: weeks
        median (confidence interval 95%)
    999 (31.3 to 9999)
    45.4 (19.0 to 9999)
    Statistical analysis title
    		 MTPS9579A (1800 mg) versus Placebo
    Comparison groups
    MTPS9579A, 1800 mg v Placebo
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.6835
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 1.47

    Secondary: Rate of Asthma Exacerbations

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    End point title
    		 Rate of Asthma Exacerbations
    End point description
    The number of asthma exacerbations per year was reported for this outcome measure. Asthma exacerbation was defined as new or increased asthma symptoms (wheezing, coughing, dyspnea, chest tightness, and/or nighttime awakenings due to these symptoms) that resulted in one or both of the following: Hospitalization or emergency department visit with administration of systemic corticosteroid treatment; Treatment with systemic corticosteroids for at least 3 days, or a long-acting depot corticosteroid preparation with a therapeutic effectiveness of at least 3 days. Poisson regression was used for the analysis. mITT population included all randomised participants who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Randomisation [Week 2] to Week 50
    End point values
    		 MTPS9579A, 1800 mg Placebo
    Number of subjects analysed
    69
    65
    Units: Asthma exacerbations per patient-year
        number (not applicable)
    0.4689
    0.4267
    Statistical analysis title
    		 MTPS9579A (1800 mg) versus Placebo
    Comparison groups
    MTPS9579A, 1800 mg v Placebo
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.7648
    Method
    		 Poisson regression
    Parameter type
    		 Rate Ratio
    Point estimate
    1.0989
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5925
         upper limit
    		 2.0381

    Secondary: Absolute Change From Randomisation in Pre-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1) at Week 50

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    End point title
    		 Absolute Change From Randomisation in Pre-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1) at Week 50
    End point description
    FEV1 is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Estimates are based on a mixed model for repeated measures (MMRM) analysis with an unstructured covariance matrix. The model used the absolute change pre-bronchodilator FEV1 as the response variable and included terms for treatment arm, study visit, treatment arm by study visit interaction, baseline FEV1 as well as its interaction with study visit, in addition to the stratification factors: blood eosinophil level at visit 1 (<150, >=150 to <=300, >300 cells/microliter (uL)), number of asthma exacerbations requiring the use of systemic corticosteroids within the 12 months prior to the study entry (1 or >=2 events), and geographic region. Overall number of participants analysed are the number of participants available for analysis.mITT population included all randomised participants who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Randomisation [Week 2] to Week 50
    End point values
    		 MTPS9579A, 1800 mg Placebo
    Number of subjects analysed
    62
    61
    Units: liters
        arithmetic mean (standard error)
    0.11 ( 0.034 )
    0.03 ( 0.034 )
    Statistical analysis title
    		 MTPS9579A (1800 mg) versus Placebo
    Comparison groups
    MTPS9579A, 1800 mg v Placebo
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.125
    Method
    		 Mixed model for repeated measures (MMRM)
    Confidence interval

    Secondary: Time to First Asthma Exacerbation

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    End point title
    		 Time to First Asthma Exacerbation
    End point description
    The time from randomisation to first asthma exacerbation was measured. Asthma exacerbation was defined as new or increased asthma symptoms (wheezing, coughing, dyspnea, chest tightness, and/or nighttime awakenings due to these symptoms) that resulted in one or both of the following: Hospitalization or emergency department visit with administration of systemic corticosteroid treatment; Treatment with systemic corticosteroids for at least 3 days, or a long-acting depot corticosteroid preparation with a therapeutic effectiveness of at least 3 days. 99999=The data for median, lower and upper limit of CI was not estimable due to insufficient number of participants with events. Cox regression was used for the analysis. mITT population included all randomised participants who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Randomisation [Week 2] to Week 50
    End point values
    		 MTPS9579A, 1800 mg Placebo
    Number of subjects analysed
    69
    65
    Units: weeks
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    		 MTPS9579A (1800 mg) versus Placebo
    Comparison groups
    MTPS9579A, 1800 mg v Placebo
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5248
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 1.54

    Secondary: Absolute Change From Randomisation in Fractional Exhaled Nitric Oxide (FeNO) at Week 50

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    End point title
    		 Absolute Change From Randomisation in Fractional Exhaled Nitric Oxide (FeNO) at Week 50
    End point description
    FeNO is a volatile marker of airway inflammation that decreases with inhaled corticosteroid treatment. The measurements recorded were according to standardized procedures by the American Thoracic Society. Estimates are based on a MMRM analysis with an unstructured covariance matrix. The model used the absolute change pre-bronchodilator FeNO as the response variable and included terms for treatment arm, study visit, treatment arm by study visit interaction, baseline FeNO as well as its interaction with study visit, in addition to the stratification factors: blood eosinophil level at visit 1 (<150, >=150 to <=300, >300 cells/uL), number of asthma exacerbations requiring the use of systemic corticosteroids within the 12 months prior to the study entry (1 or >=2 events), and geographic region. Overall number of participants analysed are the number of participants available for analysis.mITT population included all randomised participants who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Randomisation [Week 2] to Week 50
    End point values
    		 MTPS9579A, 1800 mg Placebo
    Number of subjects analysed
    57
    54
    Units: parts per billion (ppb)
        arithmetic mean (standard error)
    -1.67 ( 2.722 )
    -1.52 ( 2.791 )
    Statistical analysis title
    		 MTPS9579A (1800 mg) versus Placebo
    Comparison groups
    MTPS9579A, 1800 mg v Placebo
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.9693
    Method
    		 Mixed model for repeated measures (MMRM)
    Confidence interval

    Secondary: Relative Percent Change From Randomisation in Pre-Bronchodilator FEV1 at Week 50

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    End point title
    		 Relative Percent Change From Randomisation in Pre-Bronchodilator FEV1 at Week 50
    End point description
    FEV1 was the volume of air exhaled in the first second of a forced exhalation as measured by spirometer. Estimates are based on a MMRM analysis with an unstructured covariance matrix. The Model used the relative change pre-bronchodilator FEV1 as response variable and included terms for treatment arm, study visit, treatment arm by study visit interaction, baseline FEV1 as well as its interaction with study visit, in addition to the stratification factors: blood eosinophil level at visit 1 (<150, >=150 to <=300, >300 cells/uL), number of asthma exacerbations requiring the use of systemic corticosteroids within 12 months prior to study entry (1 or >=2 events), and geographic region. Relative change (%) in FEV1 = (absolute change in FEV1 / baseline FEV1) x 100. Overall number of participants analysed are the number of participants available for analysis. mITT population included all randomised participants who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Randomisation [Week 2] to Week 50
    End point values
    		 MTPS9579A, 1800 mg Placebo
    Number of subjects analysed
    62
    61
    Units: percent change
        arithmetic mean (standard error)
    6.44 ( 1.894 )
    3.15 ( 1.921 )
    Statistical analysis title
    		 MTPS9579A (1800 mg) versus Placebo
    Comparison groups
    MTPS9579A, 1800 mg v Placebo
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2249
    Method
    		 Mixed model for repeated measures (MMRM)
    Confidence interval

    Secondary: Percentage of Participants with Adverse Events

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    End point title
    		 Percentage of Participants with Adverse Events
    End point description
    An adverse event (AE) is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not considered related to the medicinal (investigational) product.The safety analysis population included all randomised participants who received at least one dose of study drug during the 48-week double-blind treatment period.
    End point type
    Secondary
    End point timeframe
    Up to approximately Week 58
    End point values
    		 MTPS9579A, 1800 mg Placebo
    Number of subjects analysed
    69
    65
    Units: percentage of participants
        number (not applicable)
    79.7
    86.2
    No statistical analyses for this end point

    Secondary: Area Under Concentration-Time Curve for the First Dosing Interval (AUClast) of MTPS9579A

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    End point title
    		 Area Under Concentration-Time Curve for the First Dosing Interval (AUClast) of MTPS9579A [1]
    End point description
    PK-evaluable population includes all participants who had at least one evaluable PK sample.
    End point type
    Secondary
    End point timeframe
    Randomization [Week 2] to Week 6
    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: This endpoint measures pharmacokinetic parameter which is analysed only in the MTPS9579A group.
    End point values
    		 MTPS9579A, 1800 mg
    Number of subjects analysed
    69
    Units: day*ug/mL
        geometric mean (geometric coefficient of variation)
    5263.14 ( 83.6 )
    No statistical analyses for this end point

    Secondary: Relative Percent Change From Randomisation in FeNO at Week 50

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    End point title
    		 Relative Percent Change From Randomisation in FeNO at Week 50
    End point description
    FeNO is a volatile marker of airway inflammation that decreases with inhaled corticosteroid treatment. Relative change (%) in FeNO = (absolute change in FeNO / baseline FeNO) x 100. Estimates are based on a MMRM analysis with an unstructured covariance matrix. Model used absolute change pre-bronchodilator FeNO as the response variable and included terms for treatment arm, study visit, treatment arm by study visit interaction, baseline FeNO as well as its interaction with study visit, in addition to the stratification factors: blood eosinophil level at visit 1 (<150, >=150 to <=300, >300 cells/uL), number of asthma exacerbations requiring the use of systemic corticosteroids within 12 months prior to study entry (1 or >=2 events), and geographic region. Overall number of participants analysed are the number of participants available for analysis. mITT population included all randomised participants who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Randomisation [Week 2] to Week 50
    End point values
    		 MTPS9579A, 1800 mg Placebo
    Number of subjects analysed
    57
    54
    Units: percent change
        arithmetic mean (standard error)
    26.02 ( 10.223 )
    26.29 ( 10.482 )
    Statistical analysis title
    		 MTPS9579A (1800 mg) versus Placebo
    Comparison groups
    MTPS9579A, 1800 mg v Placebo
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.9855
    Method
    		 Mixed model for repeated measures (MMRM)
    Confidence interval

    Secondary: Maximum Serum Concentration (Cmax) for the First Dosing Interval of MTPS9579A

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    End point title
    		 Maximum Serum Concentration (Cmax) for the First Dosing Interval of MTPS9579A [2]
    End point description
    PK-evaluable population includes all participants who had at least one evaluable PK sample.
    End point type
    Secondary
    End point timeframe
    2-hour post-dose on Week 2
    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 measures pharmacokinetic parameter which is analysed only in the MTPS9579A group.
    End point values
    		 MTPS9579A, 1800 mg
    Number of subjects analysed
    69
    Units: ug/mL
        geometric mean (geometric coefficient of variation)
    419 ( 51.4 )
    No statistical analyses for this end point

    Secondary: Steady State Cmax of MTPS9579A

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    End point title
    		 Steady State Cmax of MTPS9579A [3]
    End point description
    PK-evaluable population includes all participants who had at least one evaluable PK sample.
    End point type
    Secondary
    End point timeframe
    2-hour post-dose on Week 14
    Notes
    [3] - 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 measures pharmacokinetic parameter which is analysed only in the MTPS9579A group.
    End point values
    		 MTPS9579A, 1800 mg
    Number of subjects analysed
    69
    Units: ug/mL
        geometric mean (geometric coefficient of variation)
    735 ( 31 )
    No statistical analyses for this end point

    Secondary: Steady State Ctrough of MTPS9579A

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    End point title
    		 Steady State Ctrough of MTPS9579A [4]
    End point description
    PK-evaluable population includes all participants who had at least one evaluable PK sample.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Week 14
    Notes
    [4] - 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 measures pharmacokinetic parameter which is analysed only in the MTPS9579A group.
    End point values
    		 MTPS9579A, 1800 mg
    Number of subjects analysed
    69
    Units: ug/mL
        geometric mean (geometric coefficient of variation)
    226 ( 45.4 )
    No statistical analyses for this end point

    Secondary: Trough Serum Concentration (Ctrough) Accumulation Ratio of MTPS9579A

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    End point title
    		 Trough Serum Concentration (Ctrough) Accumulation Ratio of MTPS9579A [5]
    End point description
    The accumulation ratio is calculated by taking the individual ratio of the Ctrough at Week 14 to the Ctrough at Week 6. PK-evaluable population includes all participants who had at least one evaluable PK sample.
    End point type
    Secondary
    End point timeframe
    Predose on Weeks 6 and 14
    Notes
    [5] - 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 measures pharmacokinetic parameter which is analysed only in the MTPS9579A group.
    End point values
    		 MTPS9579A, 1800 mg
    Number of subjects analysed
    69
    Units: ratio
        geometric mean (geometric coefficient of variation)
    1.92 ( 28.3 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Anti-Drug Antibodies (ADA) to MTPS9579A

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    End point title
    		 Percentage of Participants With Anti-Drug Antibodies (ADA) to MTPS9579A
    End point description
    Treatment Emergent ADA is (a) negative or missing baseline ADA result(s) and at least one positive post-baseline ADA result, OR (b) positive ADA result at baseline and one or more post-baseline titer results that are at least 0.60 titer unit (t.u.) greater than the baseline titer result. The immunogenicity analysis population included all participants with at least one ADA assessment.
    End point type
    Secondary
    End point timeframe
    Pre-dose Week 54
    End point values
    		 MTPS9579A, 1800 mg Placebo
    Number of subjects analysed
    68
    65
    Units: percentage of participants
        number (not applicable)
    5.9
    0
    No statistical analyses for this end point

    Secondary: Maximum Time to Serum Concentration (Tmax) of MTPS9579A

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    End point title
    		 Maximum Time to Serum Concentration (Tmax) of MTPS9579A [6]
    End point description
    PK-evaluable population includes all participants who had at least one evaluable PK sample.
    End point type
    Secondary
    End point timeframe
    Pre-dose and 2-hour post-dose on Weeks 2, 6, 10, 14, 22, 30, 38; and pre-dose on Weeks 3, 50, and Week 54 or ET visit
    Notes
    [6] - 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 measures pharmacokinetic parameter which is analysed only in the MTPS9579A group.
    End point values
    		 MTPS9579A, 1800 mg
    Number of subjects analysed
    69
    Units: day
        median (standard deviation)
    0.12 ( 3.14 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately Week 58
    Adverse event reporting additional description
    Safety analysis population included all randomized participants who received at least one dose of study drug during the 48-week double-blind treatment period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    MTPS9579A, 1800 mg
    Reporting group description
    		 Participants with uncontrolled moderate to severe asthma received Placebo, given as IV infusion, for 14 days in the Placebo run-in period. Participants then received MTPS9579A, 1800 mg, given as IV infusion at randomization (Week 2), Week 6, and every 4 weeks thereafter through Week 46.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants with uncontrolled moderate to severe asthma received Placebo, given as IV infusion, for 14 days in the Placebo run-in period. Participants received MTPS9579A matching placebo, given as IV infusion at randomization (Week 2), Week 6, and every 4 weeks thereafter through Week 46.

    Serious adverse events
    		 MTPS9579A, 1800 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 69 (7.25%)
    4 / 65 (6.15%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Tendon injury
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 65 (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
    Accidental death
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 65 (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 pneumonia
         subjects affected / exposed
    0 / 69 (0.00%)
    3 / 65 (4.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    COVID-19
         subjects affected / exposed
    1 / 69 (1.45%)
    1 / 65 (1.54%)
         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: 5%
    Non-serious adverse events
    		 MTPS9579A, 1800 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    32 / 69 (46.38%)
    38 / 65 (58.46%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 69 (7.25%)
    3 / 65 (4.62%)
         occurrences all number
    6
    3
    Respiratory, thoracic and mediastinal disorders
    Rhinitis allergic
         subjects affected / exposed
    0 / 69 (0.00%)
    4 / 65 (6.15%)
         occurrences all number
    0
    5
    Asthma
         subjects affected / exposed
    19 / 69 (27.54%)
    24 / 65 (36.92%)
         occurrences all number
    31
    33
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 69 (4.35%)
    4 / 65 (6.15%)
         occurrences all number
    3
    4
    Back pain
         subjects affected / exposed
    1 / 69 (1.45%)
    4 / 65 (6.15%)
         occurrences all number
    1
    4
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    4 / 69 (5.80%)
    5 / 65 (7.69%)
         occurrences all number
    5
    5
    COVID-19
         subjects affected / exposed
    6 / 69 (8.70%)
    6 / 65 (9.23%)
         occurrences all number
    6
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Aug 2019
    Inclusion criteria modified to remove requirement for FEV1/FVC < 70%. Safety follow-up reporting period now includes a safety follow-up telephone call at Week (Wk) 58. Requirement for gram staining of urine specimens, if clinically indicated, has been removed. Additional details on prospective monitoring for anaphylaxis have been provided. For participants who discontinue study drug but remain on study, it has been clarified that adverse event reporting should continue through end of the study (not only 84 days after the final dose of study drug). More detail has been provided for efficacy analyses calculations to clarify baseline calculation for the primary efficacy analysis and secondary efficacy analyses calculations.
    22 Nov 2019
    The requirement of documented history of asthma exacerbation within 12 months prior to screening has been increased from ≥1 to ≥2. Participants must be on daily maintenance ICS during prior exacerbations, but requirement that this ICS dose be at the same/higher dose as at screening has been removed. The in-person safety follow-up visit has been moved from 6 weeks to 8 weeks after the final dose of study drug. Language has been modified to better explain that within a single screening period, participants who did not meet the requirement of pre-bronchodilator FEV1 of 40%−80% or post-bronchodilator reversibility of FEV1 (liters) of ≥12% and ≥ 200 mL are allowed up to two additional attempts to meet these two eligibility criteria, but only if their prebronchodilator FEV1 was between 35% and 85%. The requirement that pre bronchodilator testing must be performed in morning has been removed. Smoking exclusion criterion has been clarified to include e-cigarettes or vaping use. To allow for ECGs to be collected 3 hours or more from participant's’ last meal, the requirement that ECGs be obtained prior to other assessments has been removed.
    18 Sep 2021
    Text regarding the interim analyses (planned and optional) has been updated to reflect that enrollment may be permanently halted. Participants already enrolled continued to be treated and monitored per protocol. To accommodate the interim analyses, text regarding the requirements for the database to be frozen and cleaned has been removed. It has been clarified that urine biomarkers are to be collected pre-dose and that post-dose PK samples are to be collected 2 hours±30 minutes after the end of the dose.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    08 Apr 2020
    Enrollment was initially halted on 08 April 2020 in response to the emerging pandemic and concerns regarding data integrity (e.g., missed study doses and visits).
    22 Jun 2020

    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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