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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled, parallel-group, 12-week Proof-of-Concept study to assess the efficacy, safety, and tolerability of rilzabrutinib in participants with moderate-to-severe asthma who are not well controlled on inhaled corticosteroid plus long-acting β2 adrenergic agonist therapy

    Summary
    EudraCT number
    		 2021-002490-26
    Trial protocol
    		 ES   PL   HU   BG  
    Global end of trial date
    28 Feb 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Mar 2025
    First version publication date
    15 Mar 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ACT17208
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05104892
    WHO universal trial number (UTN)
    		 U1111-1262-2956
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    82 Avenue Raspail, Gentilly, France, 94250
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.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 May 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Feb 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effects of rilzabrutinib compared to placebo on reducing the incidence of “loss of asthma control” (LOAC) events.
    Protection of trial subjects
    Participants were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the participant and considering the local culture. During the course of the trial, participants were provided with individual participant cards indicating the nature of the trial the participant is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the law governing personal data protection in force in all countries in which it operates.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Dec 2021
    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: 58
    Country: Number of subjects enrolled
    Bulgaria: 50
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Chile: 26
    Country: Number of subjects enrolled
    Hungary: 10
    Country: Number of subjects enrolled
    Korea, Republic of: 6
    Country: Number of subjects enrolled
    Mexico: 4
    Country: Number of subjects enrolled
    Poland: 15
    Country: Number of subjects enrolled
    Romania: 17
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    Türkiye: 2
    Country: Number of subjects enrolled
    Ukraine: 1
    Country: Number of subjects enrolled
    United Kingdom: 1
    Worldwide total number of subjects
    196
    EEA total number of subjects
    97
    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)
    170
    From 65 to 84 years
    26
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 48 centers in 13 countries. A total of 310 participants were screened between 12 December 2021 and 14 November 2023, of which 114 were screen failures. Screen failures were mainly due to not meeting the eligibility criteria.

    Pre-assignment
    Screening details
    		 A total of 196 participants were randomized. Randomization was stratified by immunoglobulin E levels [(IgE) <100 international units per milliliter (IU/mL) or >=100 IU/mL] and region. Assignment to arms was done centrally using interactive response technology (IRT) in 1:1 ratio.

    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
    		 Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo BID
    Arm description
    		 Participants were administered placebo orally twice daily (BID) on Day 1 for 12 weeks, added to background therapy of inhaled corticosteroids/long-acting beta 2-adrenergic agonist (ICS/LABA) fluticasone/salmeterol combination therapy at stable dose for 4 weeks. Salmeterol was withdrawn at Week 4; fluticasone was administered up to Week 9 and gradually withdrawn from Week 6.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were administered placebo orally BID, with or without food starting on Day 1.

    Investigational medicinal product name
    Salmeterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants were administered 1 puff via DPI or 2 puffs via MDI at a stable dose until Week 4.

    Investigational medicinal product name
    Fluticasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants were administered 1 puff via dry powder inhaler (DPI) or 2 puff via metered dose inhaler (MDI) up to Week 9 and gradually withdrawn from Week 6.

    Arm title
    		 Rilzabrutinib 400 mg BID
    Arm description
    		 Participants were administered rilzabrutinib 400 milligram (mg) orally BID on Day 1 for 12 weeks added to background therapy of ICS/LABA, fluticasone/salmeterol combination therapy at stable dose for 4 weeks. Salmeterol was withdrawn at Week 4; fluticasone was administered up to Week 9 and gradually withdrawn from Week 6.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rilzabrutinib
    Investigational medicinal product code
    SAR444671
    Other name
    PRN1008
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were administered rilzabrutinib orally BID, with or without food starting on Day 1.

    Investigational medicinal product name
    Salmeterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants were administered 1 puff via DPI or 2 puffs via MDI at a stable dose until Week 4.

    Investigational medicinal product name
    Fluticasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants were administered 1 puff via DPI or 2 puff via MDI up to Week 9 and gradually withdrawn from Week 6.

    Arm title
    		 Placebo TID
    Arm description
    		 Participants were administered placebo orally three times a day (TID) on Day 1 for 12 weeks added to background therapy of ICS/LABA, fluticasone/salmeterol combination therapy at stable dose for 4 weeks. Salmeterol was withdrawn at Week 4; fluticasone was administered up to Week 9 and gradually withdrawn from Week 6.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were administered placebo orally TID, with or without food starting on Day 1.

    Investigational medicinal product name
    Salmeterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants were administered 1 puff via DPI or 2 puffs via MDI at a stable dose until Week 4.

    Investigational medicinal product name
    Fluticasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants were administered 1 puff via DPI or 2 puff via MDI up to Week 9 and gradually withdrawn from Week 6.

    Arm title
    		 Rilzabrutinib 400 mg TID
    Arm description
    		 Participants were administered rilzabrutinib 400 mg orally TID on Day 1 for 12 weeks added to background therapy of ICS/LABA, fluticasone/salmeterol combination therapy at stable dose for 4 weeks. Salmeterol was withdrawn at Week 4; fluticasone was administered up to Week 9 and gradually withdrawn from Week 6.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rilzabrutinib
    Investigational medicinal product code
    SAR444671
    Other name
    PRN1008
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were administered rilzabrutinib orally TID, with or without food starting on Day 1.

    Investigational medicinal product name
    Salmeterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants were administered 1 puff via DPI or 2 puffs via MDI at a stable dose until Week 4.

    Investigational medicinal product name
    Fluticasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants were administered 1 puff via DPI or 2 puff via MDI up to Week 9 and gradually withdrawn from Week 6.

    Number of subjects in period 1
    		Placebo BID Rilzabrutinib 400 mg BID Placebo TID Rilzabrutinib 400 mg TID
    Started
    32
    32
    68
    64
    Completed
    31
    30
    67
    60
    Not completed
    1
    2
    1
    4
         Consent withdrawn by subject
    -
    -
    1
    4
         Adverse event, non-fatal
    -
    1
    -
    -
         Poor compliance to protocol
    1
    -
    -
    -
         Sponsor decision
    -
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo BID
    Reporting group description
    		 Participants were administered placebo orally twice daily (BID) on Day 1 for 12 weeks, added to background therapy of inhaled corticosteroids/long-acting beta 2-adrenergic agonist (ICS/LABA) fluticasone/salmeterol combination therapy at stable dose for 4 weeks. Salmeterol was withdrawn at Week 4; fluticasone was administered up to Week 9 and gradually withdrawn from Week 6.

    Reporting group title
    Rilzabrutinib 400 mg BID
    Reporting group description
    		 Participants were administered rilzabrutinib 400 milligram (mg) orally BID on Day 1 for 12 weeks added to background therapy of ICS/LABA, fluticasone/salmeterol combination therapy at stable dose for 4 weeks. Salmeterol was withdrawn at Week 4; fluticasone was administered up to Week 9 and gradually withdrawn from Week 6.

    Reporting group title
    Placebo TID
    Reporting group description
    		 Participants were administered placebo orally three times a day (TID) on Day 1 for 12 weeks added to background therapy of ICS/LABA, fluticasone/salmeterol combination therapy at stable dose for 4 weeks. Salmeterol was withdrawn at Week 4; fluticasone was administered up to Week 9 and gradually withdrawn from Week 6.

    Reporting group title
    Rilzabrutinib 400 mg TID
    Reporting group description
    		 Participants were administered rilzabrutinib 400 mg orally TID on Day 1 for 12 weeks added to background therapy of ICS/LABA, fluticasone/salmeterol combination therapy at stable dose for 4 weeks. Salmeterol was withdrawn at Week 4; fluticasone was administered up to Week 9 and gradually withdrawn from Week 6.

    Reporting group values
    		 Placebo BID Rilzabrutinib 400 mg BID Placebo TID Rilzabrutinib 400 mg TID Total
    Number of subjects
    		 32 32 68 64 196
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 50.8 ( 12.3 ) 48.0 ( 13.4 ) 48.6 ( 13.7 ) 48.8 ( 13.3 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 24 18 41 39 122
        Male
    		 8 14 27 25 74
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 1 0 1 0 2
        Asian
    		 2 2 2 0 6
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0
        Black or African American
    		 0 0 1 0 1
        White
    		 29 30 64 64 187
        More than one race
    		 0 0 0 0 0
        Unknown or Not Reported
    		 0 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Placebo BID
    Reporting group description
    		 Participants were administered placebo orally twice daily (BID) on Day 1 for 12 weeks, added to background therapy of inhaled corticosteroids/long-acting beta 2-adrenergic agonist (ICS/LABA) fluticasone/salmeterol combination therapy at stable dose for 4 weeks. Salmeterol was withdrawn at Week 4; fluticasone was administered up to Week 9 and gradually withdrawn from Week 6.

    Reporting group title
    Rilzabrutinib 400 mg BID
    Reporting group description
    		 Participants were administered rilzabrutinib 400 milligram (mg) orally BID on Day 1 for 12 weeks added to background therapy of ICS/LABA, fluticasone/salmeterol combination therapy at stable dose for 4 weeks. Salmeterol was withdrawn at Week 4; fluticasone was administered up to Week 9 and gradually withdrawn from Week 6.

    Reporting group title
    Placebo TID
    Reporting group description
    		 Participants were administered placebo orally three times a day (TID) on Day 1 for 12 weeks added to background therapy of ICS/LABA, fluticasone/salmeterol combination therapy at stable dose for 4 weeks. Salmeterol was withdrawn at Week 4; fluticasone was administered up to Week 9 and gradually withdrawn from Week 6.

    Reporting group title
    Rilzabrutinib 400 mg TID
    Reporting group description
    		 Participants were administered rilzabrutinib 400 mg orally TID on Day 1 for 12 weeks added to background therapy of ICS/LABA, fluticasone/salmeterol combination therapy at stable dose for 4 weeks. Salmeterol was withdrawn at Week 4; fluticasone was administered up to Week 9 and gradually withdrawn from Week 6.

    Primary: Percentage of Participants With an Loss of Asthma Control (LOAC) Event

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    End point title
    		 Percentage of Participants With an Loss of Asthma Control (LOAC) Event
    End point description
    An LOAC event was a deterioration of asthma defined as any of the following: A 30% or greater reduction from baseline in morning peak expiratory flow (PEF) on 2 consecutive days. >= 6 additional reliever puffs of salbutamol/albuterol or levosalbutamol/levalbuterol in 24 hours (compared to baseline) on 2 consecutive days. Increase in inhaled corticosteroid (ICS) >= 4 times the last prescribed ICS dose. Required use of systemic (oral and/or parenteral) steroid treatment. Required hospitalization or emergency room visit for asthma exacerbation. The baseline is defined as the available value on the latest date up to the randomization date or the first double-blind study treatment date whichever occurs earlier. The modified intent-to-treat (mITT) included all randomized participants who received at least 1 dose of study treatment analyzed according to the treatment group allocated by randomization.
    End point type
    Primary
    End point timeframe
    Up to Week 12
    End point values
    		 Placebo BID Rilzabrutinib 400 mg BID Placebo TID Rilzabrutinib 400 mg TID
    Number of subjects analysed
    32
    32
    68
    64
    Units: percentage of participants
        number (not applicable)
    50.0
    37.5
    29.4
    18.8
    Statistical analysis title
    		 Placebo BID versus rilzabrutinib BID
    Statistical analysis description
    Derived from logistic regression with study treatment group, baseline IgE strata level, region (Latin America versus Rest of the world in BID cohort), and number of exacerbation events within 2 years prior to screening.
    Comparison groups
    Placebo BID v Rilzabrutinib 400 mg BID
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.288
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.202
         upper limit
    		 1.608
    Statistical analysis title
    		 Placebo TID versus rilzabrutinib TID
    Statistical analysis description
    Derived from logistic regression with study intervention group, baseline IgE strata level, region (Eastern Europe versus Rest of the world in TID cohort), and number of exacerbation events within 2 years prior to screening.
    Comparison groups
    Placebo TID v Rilzabrutinib 400 mg TID
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2083
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.584
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.253
         upper limit
    		 1.349

    Secondary: Change From Baseline in Pre-Bronchodilator Forced Expiratory Volume in one Second (FEV1) at Week 12

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    End point title
    		 Change From Baseline in Pre-Bronchodilator Forced Expiratory Volume in one Second (FEV1) at Week 12
    End point description
    Spirometry is a standard test to measure the participant’s lung function. It was performed in accordance with the American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines. The FEV1 was the volume of air exhaled from the lungs in the first second of a forced expiration. Spirometry was performed in the morning. The baseline is defined as the available value on the latest date up to the randomization date or the first double-blind study treatment date whichever occurs earlier. The mITT included all randomized participants who received at least 1 dose of study treatment analyzed according to the treatment group allocated by randomization. Only participants with data collected at Baseline and Week 12 are reported.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Week 12
    End point values
    		 Placebo BID Rilzabrutinib 400 mg BID Placebo TID Rilzabrutinib 400 mg TID
    Number of subjects analysed
    25
    25
    54
    48
    Units: liters
        arithmetic mean (standard deviation)
    -0.06 ( 0.22 )
    -0.04 ( 0.39 )
    -0.06 ( 0.31 )
    -0.15 ( 0.27 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Post-Bronchodilator Forced Expiratory Volume in one Second at Week 12

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    End point title
    		 Change From Baseline in Post-Bronchodilator Forced Expiratory Volume in one Second at Week 12
    End point description
    Spirometry is a standard test to measure the participant’s lung function. It was performed in accordance with the ATS/ERS guidelines. The FEV1 was the volume of air exhaled from the lungs in the first second of a forced expiration as measured by spirometer. After the measurement of pre-bronchodilator FEV1, participants received 2-4 puffs of albuterol/salbutamol or levalbuterol/levosalbutamol. Post- bronchodilator FEV1 referred to the spirometry performed within 30 minutes after administration of bronchodilator. The baseline is defined as the available value on the latest date up to the randomization date or the first double-blind study treatment date whichever occurs earlier. The mITT included all randomized participants who received at least 1 dose of study treatment analyzed according to the treatment group allocated by randomization. Only participants with data collected at Baseline and Week 12 are reported.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Week 12
    End point values
    		 Placebo BID Rilzabrutinib 400 mg BID Placebo TID Rilzabrutinib 400 mg TID
    Number of subjects analysed
    25
    26
    55
    43
    Units: liters
        arithmetic mean (standard deviation)
    -0.08 ( 0.28 )
    -0.01 ( 0.27 )
    -0.04 ( 0.32 )
    -0.10 ( 0.22 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Pre-Bronchodilator and Post-Bronchodilator Forced Expiratory Volume in one Second Over Time

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    End point title
    		 Change From Baseline in Pre-Bronchodilator and Post-Bronchodilator Forced Expiratory Volume in one Second Over Time
    End point description
    Spirometry is a standard test to measure the participant’s lung function. It was performed in accordance with the ATS/ERS guidelines. The FEV1 was the volume of air exhaled from the lungs in the first second of a forced expiration as measured by spirometer. Spirometry was performed in morning. After the measurement of pre-bronchodilator FEV1, participants received 2-4 puffs of albuterol/salbutamol or levalbuterol/levosalbutamol. Post- bronchodilator FEV1 referred to the spirometry performed within 30 minutes after administration of bronchodilator. The baseline is defined as the available value on the latest date up to the randomization date or the first double-blind study treatment date whichever occurs earlier. mITT included all randomized participants who received at least 1 dose of study treatment analyzed. Only n=number of participants with data collected at specified times for specified categories are reported. 9999 indicates no participants evaluated at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Weeks 2, 4, 6, 8, and 10
    End point values
    		 Placebo BID Rilzabrutinib 400 mg BID Placebo TID Rilzabrutinib 400 mg TID
    Number of subjects analysed
    29
    29
    63
    55
    Units: Liter
    arithmetic mean (standard deviation)
        Week 2: Pre-bronchodilator FEV1,(n = 29,26,63,55)
    0.07 ( 0.29 )
    0.08 ( 0.29 )
    0.01 ( 0.20 )
    -0.04 ( 0.25 )
        Week 4: Pre-bronchodilator FEV1,(n = 26,26,55,51)
    0.08 ( 0.28 )
    0.07 ( 0.24 )
    -0.04 ( 0.30 )
    0.02 ( 0.22 )
        Week 6: Pre-bronchodilator FEV1,(n = 29,24,57,53)
    0.05 ( 0.32 )
    0.09 ( 0.38 )
    -0.08 ( 0.24 )
    -0.07 ( 0.34 )
        Week 8: Pre-bronchodilator FEV1,(n = 27,23,55,44)
    0.02 ( 0.26 )
    0.04 ( 0.41 )
    -0.11 ( 0.22 )
    -0.12 ( 0.40 )
        Week 10: Pre-bronchodilator FEV1,(n = 27,20,53,50)
    0.00 ( 0.28 )
    0.13 ( 0.33 )
    -0.10 ( 0.28 )
    -0.10 ( 0.27 )
        Week 2: Post-bronchodilator FEV1,(n = 0,0,49,45)
    9999 ( 9999 )
    9999 ( 9999 )
    0.03 ( 0.18 )
    -0.07 ( 0.26 )
        Week 4: Post-bronchodilator FEV1,(n = 29,28,55,55)
    0.03 ( 0.25 )
    -0.01 ( 0.25 )
    -0.05 ( 0.24 )
    -0.05 ( 0.20 )
        Week 6: Post-bronchodilator FEV1,(n = 29,29,59,50)
    0.04 ( 0.30 )
    0.03 ( 0.26 )
    -0.06 ( 0.23 )
    -0.06 ( 0.19 )
        Week 8: Post-bronchodilator FEV1,(n = 28,26,53,46)
    0.02 ( 0.23 )
    0.01 ( 0.31 )
    -0.07 ( 0.25 )
    -0.08 ( 0.21 )
        Week 10: Post-bronchodilator FEV1,(n=27,27,53,50)
    0.03 ( 0.22 )
    0.10 ( 0.31 )
    -0.06 ( 0.25 )
    -0.09 ( 0.22 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Percent Predicted Forced Expiratory Volume in one Second at Week 12 (Pre-Bronchodilator and Post-Bronchodilator)

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    End point title
    		 Change from Baseline in the Percent Predicted Forced Expiratory Volume in one Second at Week 12 (Pre-Bronchodilator and Post-Bronchodilator)
    End point description
    Spirometry is a standard test to measure the participant’s lung function. It was performed in accordance with the ATS/ERS guidelines. The FEV1 was the volume of air exhaled from the lungs in first second of a forced expiration as measured by spirometer. Spirometry was performed in the morning. After the measurement of pre-bronchodilator FEV1, participants received 2-4 puffs of albuterol/salbutamol or levalbuterol/levosalbutamol. Post-bronchodilator FEV1 referred to spirometry performed within 30 minutes after administration of bronchodilator. Percent predicated FEV1 for pre and post bronchodilator is reported. The baseline is defined as the available value on the latest date up to randomization date or the first double-blind study treatment date whichever occurs earlier. The mITT included all randomized participants who received at least 1 dose of study treatment analyzed. Only n=number of participants with data collected at specified times for specified categories are reported.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Week 12
    End point values
    		 Placebo BID Rilzabrutinib 400 mg BID Placebo TID Rilzabrutinib 400 mg TID
    Number of subjects analysed
    27
    26
    59
    48
    Units: percentage of predicted FEV1
    arithmetic mean (standard deviation)
        Week 12: Pre-bronchodilator, (n = 26,25,58,48)
    -1.54 ( 7.40 )
    -2.80 ( 12.34 )
    -1.93 ( 10.31 )
    -3.35 ( 7.93 )
        Week 12: Post-bronchodilator, (n = 27,26,59,46)
    -1.48 ( 8.38 )
    -0.77 ( 8.58 )
    -1.66 ( 9.89 )
    -3.87 ( 7.30 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Forced Vital Capacity (FVC) Over Time

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    End point title
    		 Change From Baseline in the Forced Vital Capacity (FVC) Over Time
    End point description
    Spirometry is a standard test to measure the participant’s lung function. It was performed in accordance with the ATS/ERS guidelines. FVC measures the total volume of air that a participant can breathe out forcefully from a full breath, blowing all of it out. The baseline is defined as the available value on the latest date up to the randomization date or the first double-blind study treatment date whichever occurs earlier. The mITT included all randomized participants who received at least 1 dose of study treatment analyzed according to the treatment group allocated by randomization. Only participants with data collected at specified times are reported. Here, n=number of participants with data collected for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Weeks 2, 4, 6, 8, 10, and 12
    End point values
    		 Placebo BID Rilzabrutinib 400 mg BID Placebo TID Rilzabrutinib 400 mg TID
    Number of subjects analysed
    27
    24
    63
    55
    Units: liters
    arithmetic mean (standard deviation)
        Week 2 (n = 26,22,63,53)
    0.05 ( 0.35 )
    0.12 ( 0.32 )
    0.03 ( 0.29 )
    -0.03 ( 0.29 )
        Week 4 (n = 26, 23,55,51)
    0.05 ( 0.26 )
    0.06 ( 0.32 )
    -0.03 ( 0.35 )
    0.01 ( 0.21 )
        Week 6 (n = 25,23,58,49)
    0.03 ( 0.31 )
    0.05 ( 0.33 )
    -0.06 ( 0.34 )
    -0.02 ( 0.35 )
        Week 8 (n = 27,20,55,44)
    -0.03 ( 0.31 )
    0.02 ( 0.35 )
    -0.09 ( 0.27 )
    -0.11 ( 0.43 )
        Week 10 (n = 25,18,52,46)
    0.02 ( 0.33 )
    0.07 ( 0.38 )
    -0.07 ( 0.33 )
    -0.09 ( 0.28 )
        Week 12 (n = 26,24,54,46)
    -0.05 ( 0.26 )
    -0.10 ( 0.41 )
    -0.07 ( 0.34 )
    -0.12 ( 0.27 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Peak Expiratory Flow (PEF) Over Time

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    End point title
    		 Change From Baseline in the Peak Expiratory Flow (PEF) Over Time
    End point description
    PEF is defined as participant’s maximum speed of expiration as measured with electronic PEF meter. AM PEF was performed within 15 minutes after arising and PM PEF was performed in the evening. Baseline AM PEF is the mean AM measurement recorded for the 7 days prior to the first dose of study treatment, and baseline PM PEF is the mean PM measurement recorded for the 7 days prior to the first dose of study treatment. The baseline is defined as the available value on the latest date up to the randomization date or the first double-blind study treatment date whichever occurs earlier. The mITT population. Only participants with data collected at specified times are reported. Here, n=number of participants with data collected for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12
    End point values
    		 Placebo BID Rilzabrutinib 400 mg BID Placebo TID Rilzabrutinib 400 mg TID
    Number of subjects analysed
    32
    32
    68
    63
    Units: liter/minute
    arithmetic mean (standard deviation)
        Week 1, AM PEF (n = 32,32,68,63)
    7.90 ( 29.78 )
    6.64 ( 29.81 )
    13.99 ( 35.33 )
    9.54 ( 41.80 )
        Week 2, AM PEF (n = 32,31,68,62)
    4.42 ( 42.51 )
    5.05 ( 28.77 )
    18.37 ( 41.12 )
    12.61 ( 44.75 )
        Week 3, AM PEF (n = 31,31,68,61)
    7.15 ( 51.14 )
    9.41 ( 27.61 )
    19.34 ( 47.74 )
    14.58 ( 49.67 )
        Week 4, AM PEF (n = 31,31,68,59)
    7.68 ( 55.67 )
    13.03 ( 34.65 )
    21.78 ( 49.65 )
    13.87 ( 52.88 )
        Week 5, AM PEF (n = 30,31,68,59)
    -5.67 ( 41.75 )
    5.74 ( 48.44 )
    14.70 ( 59.89 )
    9.11 ( 66.16 )
        Week 6, AM PEF (n = 30,31,67,58)
    -10.29 ( 43.37 )
    -0.20 ( 45.61 )
    18.75 ( 66.05 )
    7.17 ( 70.72 )
        Week 7, AM PEF (n = 31,31,65,56)
    -1.87 ( 42.62 )
    3.07 ( 38.33 )
    11.45 ( 66.84 )
    6.02 ( 76.11 )
        Week 8, AM PEF (n = 30,31,63,56)
    -2.67 ( 42.98 )
    2.83 ( 43.91 )
    17.09 ( 63.60 )
    6.78 ( 78.57 )
        Week 9, AM PEF (n = 30,29,62,57)
    -7.14 ( 39.18 )
    9.56 ( 52.59 )
    12.88 ( 64.87 )
    5.73 ( 80.84 )
        Week 10, AM PEF (n = 30,30,61,55)
    -14.43 ( 46.89 )
    0.06 ( 40.14 )
    8.83 ( 63.87 )
    1.55 ( 82.02 )
        Week 11, AM PEF (n = 30,28,61,54)
    -16.21 ( 39.93 )
    -3.10 ( 45.47 )
    5.77 ( 71.21 )
    4.32 ( 76.30 )
        Week 12, AM PEF (n = 28,27,60,50)
    -15.01 ( 35.56 )
    -3.61 ( 44.25 )
    3.28 ( 74.37 )
    5.78 ( 77.70 )
        Week 1, PM PEF (n = 32,32,67,62)
    10.54 ( 29.06 )
    -1.29 ( 27.56 )
    14.26 ( 34.42 )
    5.61 ( 44.88 )
        Week 2, PM PEF (n = 32,31,67,62)
    4.41 ( 43.26 )
    -2.18 ( 34.63 )
    21.29 ( 42.63 )
    1.77 ( 50.34 )
        Week 3, PM PEF (n = 31,31,67,61)
    12.95 ( 44.39 )
    -2.20 ( 32.42 )
    21.31 ( 44.56 )
    4.28 ( 50.30 )
        Week 4, PM PEF (n = 31,31,67,58)
    6.82 ( 47.17 )
    1.34 ( 34.76 )
    21.77 ( 49.32 )
    7.46 ( 52.72 )
        Week 5, PM PEF (n = 30,31,67,57)
    -10.77 ( 33.50 )
    -14.75 ( 41.57 )
    12.93 ( 55.72 )
    -0.64 ( 65.65 )
        Week 6, PM PEF (n = 30,31,66,57)
    -8.31 ( 32.81 )
    -14.24 ( 53.62 )
    12.68 ( 60.20 )
    2.43 ( 73.08 )
        Week 7, PM PEF (n = 30,31,64,55)
    -5.19 ( 33.45 )
    -13.33 ( 39.83 )
    13.07 ( 64.55 )
    4.97 ( 81.71 )
        Week 8, PM PEF (n = 30,30,63,55)
    -5.64 ( 35.97 )
    -7.66 ( 41.46 )
    15.53 ( 59.67 )
    3.66 ( 78.98 )
        Week 9, PM PEF (n = 30,30,62,55)
    -3.45 ( 35.09 )
    -5.87 ( 57.20 )
    12.61 ( 59.34 )
    2.68 ( 83.50 )
        Week 10, PM PEF (n = 30,30,61,54)
    -16.01 ( 39.97 )
    -7.35 ( 51.10 )
    11.88 ( 60.74 )
    4.97 ( 83.30 )
        Week 11, PM PEF (n = 30,28,61,53)
    -13.09 ( 31.44 )
    -12.40 ( 56.11 )
    1.28 ( 67.54 )
    -0.47 ( 83.71 )
        Week 12, PM PEF (n = 28,26,58,49)
    -14.31 ( 34.08 )
    -16.94 ( 48.16 )
    -5.10 ( 71.12 )
    3.43 ( 87.98 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Forced Expiratory Flow [(FEV) 25-75%] Over Time

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    End point title
    		 Change From Baseline in Forced Expiratory Flow [(FEV) 25-75%] Over Time
    End point description
    Spirometry is a standard test to measure the participant’s lung function. It was performed in accordance with the ATS/ERS guidelines. FEF is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. FEF 25-75% was defined as the FEF at 25% to 75% of FVC, where FVC was defined as the total volume of air that a participant can breathe out forcefully from a full breath, blowing all of it out. The baseline is defined as the available value on the latest date up to the randomization date or the first double-blind study treatment date whichever occurs earlier. The mITT included all randomized participants who received at least 1 dose of study treatment analyzed according to the treatment group allocated by randomization. Only participants with data collected at specified times are reported. Here, n=number of participants with data collected for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Weeks 2, 4, 6, 8, 10, and 12
    End point values
    		 Placebo BID Rilzabrutinib 400 mg BID Placebo TID Rilzabrutinib 400 mg TID
    Number of subjects analysed
    30
    29
    65
    29
    Units: Liter/second
    arithmetic mean (standard deviation)
        Week 2 (n = 30,29,65,59)
    0.11 ( 0.39 )
    0.01 ( 0.34 )
    0.02 ( 0.38 )
    -0.06 ( 0.35 )
        Week 4 (n = 28,27,60,55)
    0.08 ( 0.38 )
    0.09 ( 0.33 )
    -0.03 ( 0.45 )
    0.03 ( 0.42 )
        Week 6 (n = 29,28,61,55)
    0.10 ( 0.41 )
    0.05 ( 0.49 )
    -0.11 ( 0.39 )
    -0.08 ( 0.49 )
        Week 8 (n = 27,26,59,48)
    0.03 ( 0.37 )
    0.07 ( 0.44 )
    -0.14 ( 0.41 )
    -0.15 ( 0.50 )
        Week 10 (n = 27,21,56,52)
    0.02 ( 0.36 )
    0.11 ( 0.39 )
    -0.15 ( 0.49 )
    -0.13 ( 0.49 )
        Week 12 (n = 26,25,58,48)
    -0.03 ( 0.22 )
    0.01 ( 0.38 )
    -0.13 ( 0.49 )
    -0.23 ( 0.60 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Asthma Control Questionnaire-5 (ACQ-5) Score

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    End point title
    		 Change From Baseline in Asthma Control Questionnaire-5 (ACQ-5) Score
    End point description
    The ACQ-5 is a questionnaire that measured the adequacy of asthma control and any changes in asthma control that occurred spontaneously or as a result of treatment. The ACQ-5 has 5 questions on the asthma symptoms experienced by participants during the past week and to respond on a 7-point scale for each question (0 = no impairment, 6 = maximum impairment). The ACQ-5 score is the mean of the 5 questions and total score ranged from 0 (totally controlled) to 6 (severely uncontrolled), a high score indicates low asthma control. The baseline is defined as the available value on the latest date up to the randomization date or the first double-blind study treatment date whichever occurs earlier. The mITT population. Only n=number of participants with data collected at specified times for specified categories are reported.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Weeks 2, 4, 6, 8, 10, and 12
    End point values
    		 Placebo BID Rilzabrutinib 400 mg BID Placebo TID Rilzabrutinib 400 mg TID
    Number of subjects analysed
    30
    31
    63
    61
    Units: score on a scale
    arithmetic mean (standard deviation)
        Week 2, (n = 30,30,63,61)
    -0.25 ( 0.78 )
    -0.74 ( 0.62 )
    -0.17 ( 0.62 )
    -0.37 ( 0.79 )
        Week 4, (n = 30,31,62,59)
    -0.40 ( 0.96 )
    -0.94 ( 0.64 )
    -0.23 ( 0.79 )
    -0.57 ( 0.77 )
        Week 6, (n = 28,30,60,57)
    -0.26 ( 0.99 )
    -0.97 ( 0.74 )
    -0.38 ( 0.75 )
    -0.57 ( 0.83 )
        Week 8, (n = 30,28,63,52)
    -0.56 ( 1.04 )
    -0.91 ( 0.80 )
    -0.19 ( 0.94 )
    -0.72 ( 0.73 )
        Week 10, (n = 28,27,55,56)
    -0.42 ( 1.11 )
    -0.92 ( 0.89 )
    -0.33 ( 0.90 )
    -0.75 ( 0.81 )
        Week 12, (n = 28,28,60,49)
    -0.34 ( 1.02 )
    -0.89 ( 0.93 )
    -0.22 ( 1.03 )
    -0.82 ( 0.72 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Asthma Quality of Life Questionnaire With Standardized Activities (AQLQ[S]) Self-Administered Score

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    End point title
    		 Change From Baseline in Asthma Quality of Life Questionnaire With Standardized Activities (AQLQ[S]) Self-Administered Score
    End point description
    The AQLQ (S) was a self-administered participant reported outcome (PRO) to measure the functional impairments in adult and adolescent participants. The instrument comprised of 32 items each rated on a 7-point Likert scales from 1 to 7. The AQLQ (S) has 4 domains: symptoms (12 items), activity limitation (11 items), emotional function (5 items), and environmental stimuli (4 items). The score of each domain was the mean of response to each of the questions in that domain. The overall global score was calculated as the average of the 32 questions and ranges from 1 (total impairment) to 7 (no impairment). Higher scores indicate better quality of life. The baseline is defined as the available value on the latest date up to the randomization date or the first double-blind study treatment date whichever occurs earlier. The mITT population. Only n=number of participants with data collected at specified times for specified categories are reported.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Weeks 4, 8, and 12
    End point values
    		 Placebo BID Rilzabrutinib 400 mg BID Placebo TID Rilzabrutinib 400 mg TID
    Number of subjects analysed
    30
    31
    65
    60
    Units: score on a scale
    arithmetic mean (standard deviation)
        Week 4, (n = 29,31,65,60)
    -0.03 ( 1.35 )
    0.73 ( 0.93 )
    0.19 ( 0.72 )
    0.19 ( 0.89 )
        Week 8, (n = 30,31,65,58)
    0.22 ( 1.06 )
    0.90 ( 0.85 )
    0.30 ( 0.86 )
    0.29 ( 0.74 )
        Week 12, (n = 29,29,62,53)
    0.29 ( 1.15 )
    0.84 ( 0.99 )
    0.26 ( 0.90 )
    0.46 ( 0.86 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Asthma Daytime Symptom Diary (ADSD) Score

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    End point title
    		 Change From Baseline in Asthma Daytime Symptom Diary (ADSD) Score
    End point description
    ADSD assesses asthma severity based on participant self-report of asthma core symptoms, i.e., difficulty breathing, wheezing, shortness of breath, chest tightness, chest pain, and cough. Participants were asked to complete ADSD every night before they go to bed, thinking about their asthma symptoms today, from when they got up this morning until now. ADSD is composed of 6 items rated using an 11-point numeric pain scale (NRS) that ranges from 0 = None to 10 = as bad as you can imagine. Total score was calculated by averaging all 6 items and the score ranged from 0 to 10. Higher scores indicated worse outcomes. The baseline is defined as available value on latest date up to randomization date or first double-blind study treatment date whichever occurs earlier. mITT population. Only n=number of participants with data collected at specified times for specified categories are reported.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12
    End point values
    		 Placebo BID Rilzabrutinib 400 mg BID Placebo TID Rilzabrutinib 400 mg TID
    Number of subjects analysed
    29
    28
    64
    59
    Units: score on a scale
    arithmetic mean (standard deviation)
        Week 1, (n = 29,28,64,59)
    -0.11 ( 0.71 )
    -0.18 ( 0.60 )
    -0.08 ( 0.58 )
    -0.25 ( 0.85 )
        Week 2, (n = 29,28,63,59)
    -0.30 ( 0.84 )
    -0.25 ( 0.81 )
    -0.21 ( 0.95 )
    -0.31 ( 0.93 )
        Week 3, (n = 28,28,63,58)
    -0.28 ( 0.90 )
    -0.36 ( 0.80 )
    -0.20 ( 1.09 )
    -0.38 ( 0.95 )
        Week 4, (n = 28,28,63,57)
    -0.25 ( 0.98 )
    -0.37 ( 0.77 )
    -0.24 ( 1.03 )
    -0.40 ( 0.96 )
        Week 5, (n = 27,28,63,56)
    -0.34 ( 0.84 )
    -0.26 ( 0.81 )
    -0.30 ( 1.11 )
    -0.47 ( 1.31 )
        Week 6, (n = 27,28,62,56)
    -0.42 ( 0.84 )
    -0.30 ( 0.90 )
    -0.26 ( 1.18 )
    -0.53 ( 1.30 )
        Week 7, (n = 27,28,60,55)
    -0.56 ( 0.94 )
    -0.33 ( 0.98 )
    -0.31 ( 1.26 )
    -0.40 ( 1.68 )
        Week 8, (n = 27,28,60,55)
    -0.58 ( 0.89 )
    -0.24 ( 0.99 )
    -0.25 ( 1.34 )
    -0.41 ( 1.64 )
        Week 9, (n = 27,27,58,54)
    -0.43 ( 0.89 )
    -0.35 ( 1.15 )
    -0.17 ( 1.45 )
    -0.40 ( 1.67 )
        Week 10, (n = 27,27,57,53)
    -0.13 ( 1.31 )
    -0.38 ( 1.12 )
    -0.20 ( 1.50 )
    -0.49 ( 1.72 )
        Week 11, (n = 27,26,57,51)
    -0.04 ( 1.28 )
    -0.33 ( 1.14 )
    -0.12 ( 1.61 )
    -0.52 ( 1.79 )
        Week 12, (n = 26,24,54,48)
    0.02 ( 1.25 )
    -0.24 ( 1.15 )
    -0.02 ( 1.82 )
    -0.63 ( 1.90 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Asthma Night Time Symptom Diary (ANSD) Score

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    End point title
    		 Change From Baseline in Asthma Night Time Symptom Diary (ANSD) Score
    End point description
    ANSD is a PRO measure designed to measure asthma symptoms in adult and adolescent participants diagnosed with mild to severe asthma. ANSD assesses asthma severity based on participant self-report of asthma core symptoms, i.e.,difficulty breathing, wheezing, shortness of breath, chest tightness, chest pain, and cough. Participants were asked to complete ANSD when getting up, thinking about their asthma symptoms last night from when they went to bed until now. ANSD is composed of 6 items rated using an 11-point NRS that ranges from 0 (None) to 10 (as bad as you can imagine). Total score was calculated by averaging all 6 items and therefore the score ranged from 0 to 10. Higher scores indicated worse outcomes. The baseline is defined as available value on latest date up to randomization date or first double-blind study treatment date whichever occurs earlier. The mITT population. Only n=number of participants with data collected at specified times for specified categories are reported.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12
    End point values
    		 Placebo BID Rilzabrutinib 400 mg BID Placebo TID Rilzabrutinib 400 mg TID
    Number of subjects analysed
    29
    28
    64
    61
    Units: score on a scale
    arithmetic mean (standard deviation)
        Week 1, (n = 29,28,64,61)
    -0.10 ( 0.63 )
    -0.26 ( 0.55 )
    -0.17 ( 0.59 )
    -0.36 ( 0.86 )
        Week 2, (n = 29,28,64,61)
    -0.28 ( 0.70 )
    -0.35 ( 0.73 )
    -0.22 ( 0.95 )
    -0.35 ( 0.93 )
        Week 3, (n = 28,28,63,61)
    -0.18 ( 0.79 )
    -0.44 ( 0.73 )
    -0.22 ( 1.01 )
    -0.43 ( 0.95 )
        Week 4, (n = 28,28,64,59)
    -0.27 ( 0.91 )
    -0.46 ( 0.79 )
    -0.29 ( 1.01 )
    -0.52 ( 1.01 )
        Week 5, (n = 27,28,63,59)
    -0.32 ( 0.72 )
    -0.31 ( 0.75 )
    -0.33 ( 1.08 )
    -0.50 ( 1.28 )
        Week 6, (n = 27,28,63,59)
    -0.36 ( 0.79 )
    -0.43 ( 0.82 )
    -0.25 ( 1.14 )
    -0.47 ( 1.29 )
        Week 7, (n = 28,28,60,57)
    -0.47 ( 0.84 )
    -0.35 ( 0.94 )
    -0.30 ( 1.28 )
    -0.47 ( 1.57 )
        Week 8, (n = 27,28,59,57)
    -0.53 ( 0.80 )
    -0.27 ( 0.94 )
    -0.28 ( 1.30 )
    -0.45 ( 1.46 )
        Week 9, (n = 27,27,58,57)
    -0.35 ( 0.98 )
    -0.37 ( 1.10 )
    -0.18 ( 1.40 )
    -0.48 ( 1.46 )
        Week 10, (n = 27,27,58,56)
    -0.02 ( 1.41 )
    -0.40 ( 1.07 )
    -0.22 ( 1.43 )
    -0.55 ( 1.56 )
        Week 11, (n = 27,26,57,53)
    0.07 ( 1.41 )
    -0.32 ( 1.10 )
    -0.07 ( 1.59 )
    -0.62 ( 1.69 )
        Week 12, (n = 26,25,57,50)
    0.14 ( 1.40 )
    -0.42 ( 1.13 )
    0.00 ( 1.71 )
    -0.68 ( 1.74 )
    No statistical analyses for this end point

    Secondary: Plasma Concentrations of Rilzabrutinib Over Time

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    End point title
    		 Plasma Concentrations of Rilzabrutinib Over Time [1]
    End point description
    Plasma samples were obtained and analyzed at specified timepoints for pharmacokinetic (PK) characterization of rilzabrutinib. PK population included all randomized and treated participants with at least 1 post-baseline PK sample with adequate documentation of dosing and sampling dates and times. Only n=number of participants with data collected at specified times for specified categories are reported.
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1, Weeks 2, 4, 8 and 12; 2 hour post-dose Day 1, Weeks 4, and 8
    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: Only PK population included all randomized and treated participants treated with Rilzabrutinib with at least 1 post-baseline PK sample with adequate documentation of dosing and sampling dates and times. Only n=number of participants with data collected at specified times for specified categories are reported.
    End point values
    		 Rilzabrutinib 400 mg BID Rilzabrutinib 400 mg TID
    Number of subjects analysed
    30
    63
    Units: nanogram/milliliter (ng/mL)
    arithmetic mean (standard deviation)
        Pre-dose: Day 1, (n = 30,63)
    0.07 ( 0.39 )
    0.05 ( 0.43 )
        Post-dose: 2-hour, Day 1, (n = 28,61)
    147.06 ( 127.52 )
    140.78 ( 128.23 )
        Pre-dose: Week 2, (n = 29,61)
    26.09 ( 75.62 )
    45.15 ( 104.23 )
        Pre-dose: Week 4, (n = 27,58)
    8.03 ( 23.74 )
    23.19 ( 58.40 )
        Post-dose: 2-hour, Week 4, (n = 23,58)
    215.50 ( 203.33 )
    197.25 ( 206.39 )
        Pre-dose: Week 8, (n = 23,47)
    16.01 ( 46.49 )
    17.31 ( 45.96 )
        Post-dose: 2-hour, Week 8, (n = 22,45)
    162.14 ( 148.20 )
    181.16 ( 176.80 )
        Pre-dose: Week 12, (n = 7,23)
    14.06 ( 11.64 )
    16.55 ( 48.16 )
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)

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    End point title
    		 Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)
    End point description
    Adverse event (AE): any untoward medical occurrence in participant or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. TEAEs: AEs that developed or worsened or became serious during treatment-emergent period, defined as time from first administration of study treatment (on Day 1) to last administration of study treatment + 7 days. SAE: any untoward medical occurrence that, at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. Safety population included all randomized participants who took at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    From first dose of study treatment (Day 1) up to last dose of study treatment + 7 days, approximately 91 days
    End point values
    		 Placebo BID Rilzabrutinib 400 mg BID Placebo TID Rilzabrutinib 400 mg TID
    Number of subjects analysed
    32
    32
    68
    64
    Units: participants
        TEAEs
    20
    14
    18
    26
        TESAEs
    0
    2
    0
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline in Numbers of Inhalations/day of Albuterol or Levalbuterol for Symptom Relief

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    End point title
    		 Change From Baseline in Numbers of Inhalations/day of Albuterol or Levalbuterol for Symptom Relief
    End point description
    The number of albuterol or levalbuterol inhalations were recorded daily by the participants in the electronic diary. A diary day is defined as the period beginning with an evening diary and ending with the following day’s morning Diary. A diary day was not included in the calculation if an evening or morning diary is missing. The reliever medication baseline value was the average number of puffs taken in the most recent 7 diary days before next visit. The baseline is defined as the available value on the latest date up to the randomization date or the first double-blind study treatment date whichever occurs earlier. The mITT included all randomized participants who received at least 1 dose of study treatment analyzed according to the treatment group allocated by randomization. Only n=number of participants with data collected at specified times for specified categories are reported.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12
    End point values
    		 Placebo BID Rilzabrutinib 400 mg BID Placebo TID Rilzabrutinib 400 mg TID
    Number of subjects analysed
    32
    32
    67
    62
    Units: inhalation per day
    arithmetic mean (standard deviation)
        Week 1, (n = 32,32,67,62)
    -0.50 ( 1.03 )
    -0.41 ( 1.03 )
    -0.16 ( 1.45 )
    -0.22 ( 0.68 )
        Week 2, (n = 32,31,67,62)
    -0.61 ( 1.34 )
    -0.68 ( 1.24 )
    -0.24 ( 1.38 )
    -0.26 ( 0.89 )
        Week 3, (n = 31,31,67,60)
    -0.24 ( 1.98 )
    -0.83 ( 1.48 )
    -0.26 ( 1.42 )
    -0.10 ( 0.92 )
        Week 4, (n = 31,30,67,58)
    -0.28 ( 2.14 )
    -0.81 ( 1.41 )
    -0.26 ( 1.46 )
    -0.18 ( 1.00 )
        Week 5, (n = 30,31,67,57)
    -0.39 ( 1.97 )
    -0.51 ( 1.14 )
    -0.26 ( 1.49 )
    -0.11 ( 1.11 )
        Week 6, (n = 30,31,66,57)
    -0.15 ( 1.94 )
    -0.61 ( 1.44 )
    -0.26 ( 1.49 )
    -0.18 ( 1.36 )
        Week 7, (n = 30,31,64,56)
    -0.63 ( 2.16 )
    -0.00 ( 3.35 )
    -0.01 ( 0.99 )
    0.32 ( 3.61 )
        Week 8, (n = 30,30,62,56)
    -0.68 ( 2.34 )
    -0.01 ( 3.76 )
    0.05 ( 1.40 )
    0.21 ( 3.60 )
        Week 9, (n = 30,29,61,55)
    -0.57 ( 2.40 )
    -0.07 ( 3.96 )
    0.07 ( 1.40 )
    0.08 ( 3.66 )
        Week 10, (n = 29,29,61,54)
    -0.25 ( 2.97 )
    -0.23 ( 3.88 )
    0.13 ( 1.48 )
    0.06 ( 3.74 )
        Week 11, (n = 30,27,60,53)
    0.09 ( 3.30 )
    -0.10 ( 3.99 )
    0.47 ( 2.00 )
    0.09 ( 3.76 )
        Week 12, (n = 28,26,56,49)
    0.16 ( 3.31 )
    0.26 ( 3.85 )
    1.48 ( 5.47 )
    0.16 ( 3.92 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events and all-cause mortality (death) were collected from first dose of study drug (Day 1) up to last dose of study treatment + 7 days, approximately 91 days.
    Adverse event reporting additional description
    Analysis was performed on safety population.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    Placebo BID
    Reporting group description
    		 Participants were administered placebo orally BID on Day 1 for 12 weeks, added to background therapy of ICS/LABA fluticasone/salmeterol combination therapy at stable dose for 4 weeks. Salmeterol was withdrawn at Week 4; fluticasone was administered up to Week 9 and gradually withdrawn from Week 6.

    Reporting group title
    Placebo TID
    Reporting group description
    		 Participants were administered placebo orally TID on Day 1 for 12 weeks added to background therapy of ICS/LABA, fluticasone/salmeterol combination therapy at stable dose for 4 weeks. Salmeterol was withdrawn at Week 4; fluticasone was administered up to Week 9 and gradually withdrawn from Week 6.

    Reporting group title
    Rilzabrutinib 400mg TID
    Reporting group description
    		 Participants were administered rilzabrutinib 400 mg orally TID on Day 1 for 12 weeks added to background therapy of ICS/LABA, fluticasone/salmeterol combination therapy at stable dose for 4 weeks. Salmeterol was withdrawn at Week 4; fluticasone was administered up to Week 9 and gradually withdrawn from Week 6.

    Reporting group title
    Rilzabrutinib 400mg BID
    Reporting group description
    		 Participants were administered rilzabrutinib 400 mg orally BID on Day 1 for 12 weeks added to background therapy of ICS/LABA, fluticasone/salmeterol combination therapy at stable dose for 4 weeks. Salmeterol was withdrawn at Week 4; fluticasone was administered up to Week 9 and gradually withdrawn from Week 6.

    Serious adverse events
    		 Placebo BID Placebo TID Rilzabrutinib 400mg TID Rilzabrutinib 400mg BID
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 68 (0.00%)
    0 / 64 (0.00%)
    2 / 32 (6.25%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 68 (0.00%)
    0 / 64 (0.00%)
    2 / 32 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo BID Placebo TID Rilzabrutinib 400mg TID Rilzabrutinib 400mg BID
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 32 (37.50%)
    4 / 68 (5.88%)
    12 / 64 (18.75%)
    3 / 32 (9.38%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 32 (12.50%)
    1 / 68 (1.47%)
    0 / 64 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    8
    1
    0
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 68 (0.00%)
    7 / 64 (10.94%)
    3 / 32 (9.38%)
         occurrences all number
    1
    0
    7
    3
    Respiratory, thoracic and mediastinal disorders
    Rhinitis Allergic
         subjects affected / exposed
    3 / 32 (9.38%)
    0 / 68 (0.00%)
    3 / 64 (4.69%)
    0 / 32 (0.00%)
         occurrences all number
    3
    0
    3
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    4 / 32 (12.50%)
    1 / 68 (1.47%)
    0 / 64 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    4
    1
    0
    0
    Covid-19
         subjects affected / exposed
    2 / 32 (6.25%)
    2 / 68 (2.94%)
    3 / 64 (4.69%)
    0 / 32 (0.00%)
         occurrences all number
    2
    2
    3
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Feb 2022
    This amendment was to evaluate the efficacy and safety of 2 different dose of regimens of rilzabrutinib, the current dose of 400 mg BID and an additional higher regimen of 400 mg TID in two staggered double-blind cohorts for a total number of 192 participants split. There were some editorial changes for better clarification and consistency.
    13 Sep 2022
    To update exclusion and inclusion criteria. Other minor clarifications and corrections deemed necessary by the Sponsor were also implemented.

    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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