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    Clinical Trial Results:
    A Randomized, Double-blind, Placebo-controlled, Parallel-group, 12-week Proof-of-Concept (PoC) Study to Assess the Efficacy, Safety, and Tolerability of SAR440340/REGN3500 and the Coadministration of SAR440340 and Dupilumab in Patients with Moderate-to-severe Asthma who are not well Controlled on Inhaled Corticosteroid (ICS) Plus Long-acting β2 Adrenergic Agonist (LABA) Therapy

    Summary
    EudraCT number
    		 2017-003289-29
    Trial protocol
    		 PL  
    Global end of trial date
    07 Aug 2019

    Results information
    Results version number
    		 v3(current)
    This version publication date
    04 Jan 2023
    First version publication date
    21 Aug 2020
    Other versions
    		 v1 , v2
    Version creation reason
    • Correction of full data set
    Updated safety optional field

    Trial information

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    Trial identification
    Sponsor protocol code
    ACT15102
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03387852
    WHO universal trial number (UTN)
    		 U1111-1194-2185
    Sponsors
    Sponsor organisation name
    Sanofi-aventis Recherche & Développement
    Sponsor organisation address
    1 avenue Pierre Brossolette, Chilly-Mazarin, France, 91380
    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
    07 Oct 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Aug 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effects of SAR440340 with or without dupilumab, compared to placebo, on reducing the incidence of loss of asthma control (LOAC) events.
    Protection of trial subjects
    Subjects 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 subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject was 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 laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Mar 2018
    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
    Ukraine: 63
    Country: Number of subjects enrolled
    Turkey: 26
    Country: Number of subjects enrolled
    United States: 58
    Country: Number of subjects enrolled
    Argentina: 16
    Country: Number of subjects enrolled
    Chile: 30
    Country: Number of subjects enrolled
    Mexico: 22
    Country: Number of subjects enrolled
    Poland: 37
    Country: Number of subjects enrolled
    Russian Federation: 44
    Worldwide total number of subjects
    296
    EEA total number of subjects
    37
    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)
    262
    From 65 to 84 years
    34
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted from 12-March-2018 to 7-August-2019. Subjects were screened at 70 centres across 8 countries, out of which 68 centres randomised at least 1 subject.

    Pre-assignment
    Screening details
    		 A total of 499 subjects were screened, out of which 296 subjects were enrolled and randomised to 1 of the 4 treatment groups.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Subjects received 2 subcutaneous (SC) injections of SAR440340 placebo along with 1 SC injection of dupilumab placebo once every 2 weeks (Q2W) for 12 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Matching Placebo for SAR440340
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subject received 2 SC injections of matching placebo for SAR440340 Q2W for 12 weeks. SC injection sites were to alternate between the upper thighs, 4 quadrants of the abdomen, or the upper arms, so that the same site was not injected twice during 2 consecutive visits.

    Investigational medicinal product name
    Matching Placebo for Dupilumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subject received 1 SC injection of matching placebo for dupilumab Q2W for 12 weeks. SC injection sites were to alternate between the upper thighs, 4 quadrants of the abdomen, or the upper arms, so that the same site was not injected twice during 2 consecutive visits.

    Arm title
    		 SAR440340 300 mg
    Arm description
    		 Subjects received 2 injections of SAR440340 300 milligram (mg) along with 1 injection of dupilumab placebo, SC Q2W for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    SAR440340
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subject received 2 SC injections of SAR440340 Q2W for 12 weeks. SC injection sites were to alternate between the upper thighs, 4 quadrants of the abdomen, or the upper arms, so that the same site was not injected twice during 2 consecutive visits.

    Investigational medicinal product name
    Matching Placebo for Dupilumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subject received 1 SC injection of matching placebo for dupilumab Q2W for 12 weeks. SC injection sites were to alternate between the upper thighs, 4 quadrants of the abdomen, or the upper arms, so that the same site was not injected twice during 2 consecutive visits.

    Arm title
    		 SAR440340 + Dupilumab
    Arm description
    		 Subjects received 2 injections of SAR440340 300 mg along with 1 injection of dupilumab 300 mg, SC Q2W for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    SAR440340
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subject received 2 SC injections of SAR440340 Q2W for 12 weeks. SC injection sites were to alternate between the upper thighs, 4 quadrants of the abdomen, or the upper arms, so that the same site was not injected twice during 2 consecutive visits.

    Investigational medicinal product name
    Dupilumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subject received 1 SC injection of dupilumab 300 mg Q2W for 12 weeks. SC injection sites were to alternate between the upper thighs, 4 quadrants of the abdomen or the upper arms, so that the same site was not injected twice during 2 consecutive visits.

    Arm title
    		 Dupilumab 300 mg
    Arm description
    		 Subjects received 1 injection of dupilumab 300 mg along with 2 injections of SAR440340 placebo, SC Q2W for 12 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Dupilumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subject received 1 SC injection of dupilumab 300 mg Q2W for 12 weeks. SC injection sites were to alternate between the upper thighs, 4 quadrants of the abdomen or the upper arms, so that the same site was not injected twice during 2 consecutive visits.

    Investigational medicinal product name
    Matching Placebo for SAR440340
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subject received 2 SC injections of matching placebo for SAR440340 Q2W for 12 weeks. SC injection sites were to alternate between the upper thighs, 4 quadrants of the abdomen, or the upper arms, so that the same site was not injected twice during 2 consecutive visits.

    Number of subjects in period 1
    		Placebo SAR440340 300 mg SAR440340 + Dupilumab Dupilumab 300 mg
    Started
    74
    73
    74
    75
    Treated
    74
    73
    74
    74
    Completed
    41
    55
    47
    56
    Not completed
    33
    18
    27
    19
         Randomised and not treated
    -
    -
    -
    1
         LOAC
    28
    16
    20
    14
         Other- Unspecified
    1
    1
    2
    1
         Poor compliance to protocol
    -
    -
    -
    1
         Adverse event (AE)
    3
    -
    2
    -
         Withdrawal by subject
    1
    1
    3
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received 2 subcutaneous (SC) injections of SAR440340 placebo along with 1 SC injection of dupilumab placebo once every 2 weeks (Q2W) for 12 weeks.

    Reporting group title
    SAR440340 300 mg
    Reporting group description
    		 Subjects received 2 injections of SAR440340 300 milligram (mg) along with 1 injection of dupilumab placebo, SC Q2W for 12 weeks.

    Reporting group title
    SAR440340 + Dupilumab
    Reporting group description
    		 Subjects received 2 injections of SAR440340 300 mg along with 1 injection of dupilumab 300 mg, SC Q2W for 12 weeks.

    Reporting group title
    Dupilumab 300 mg
    Reporting group description
    		 Subjects received 1 injection of dupilumab 300 mg along with 2 injections of SAR440340 placebo, SC Q2W for 12 weeks.

    Reporting group values
    		 Placebo SAR440340 300 mg SAR440340 + Dupilumab Dupilumab 300 mg Total
    Number of subjects
    		 74 73 74 75 296
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 47.0 ( 11.4 ) 49.0 ( 13.9 ) 49.1 ( 12.0 ) 51.3 ( 12.7 ) -
    Gender categorical
    Units: Subjects
        Female
    		 47 50 51 41 189
        Male
    		 27 23 23 34 107
    Race
    Units: Subjects
        White
    		 71 68 69 73 281
        Black or African American
    		 1 3 2 0 6
        Asian
    		 0 2 1 1 4
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0
        American Indian or Alaska Native
    		 2 0 1 1 4
        Multiple
    		 0 0 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received 2 subcutaneous (SC) injections of SAR440340 placebo along with 1 SC injection of dupilumab placebo once every 2 weeks (Q2W) for 12 weeks.

    Reporting group title
    SAR440340 300 mg
    Reporting group description
    		 Subjects received 2 injections of SAR440340 300 milligram (mg) along with 1 injection of dupilumab placebo, SC Q2W for 12 weeks.

    Reporting group title
    SAR440340 + Dupilumab
    Reporting group description
    		 Subjects received 2 injections of SAR440340 300 mg along with 1 injection of dupilumab 300 mg, SC Q2W for 12 weeks.

    Reporting group title
    Dupilumab 300 mg
    Reporting group description
    		 Subjects received 1 injection of dupilumab 300 mg along with 2 injections of SAR440340 placebo, SC Q2W for 12 weeks.

    Primary: Percentage of Subjects With Loss of Asthma Control

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    End point title
    		 Percentage of Subjects With Loss of Asthma Control
    End point description
    A LOAC event during the treatment period was a deterioration of asthma defined as any of the following: a) a 30 percent (%) or greater reduction from baseline in morning peak expiratory flow (PEF) on 2 consecutive days; b) greater than or equal to (>=) 6 additional reliever puffs of salbutamol/albuterol or levosalbutamol/levalbuterol in a 24-hour period (compared to baseline) on 2 consecutive days; c) increase in ICS >=4 times the last prescribed ICS dose (or >=50% of the prescribed ICS dose at Baseline if background therapy withdrawal completed); d) required use of systemic (oral and/or parenteral) steroid treatment; e) required hospitalisation or emergency room visit. The analysis was performed on modified intent-to-treat (mITT) population that included all randomised subjects who have received at least 1 dose of investigational medicinal product (IMP) analysed according to the treatment group allocated by randomisation.
    End point type
    Primary
    End point timeframe
    From Baseline up to Week 12
    End point values
    		 Placebo SAR440340 300 mg SAR440340 + Dupilumab Dupilumab 300 mg
    Number of subjects analysed
    74
    73
    74
    74
    Units: percentage of subjects
        number (not applicable)
    40.5
    21.9
    27
    18.9
    Statistical analysis title
    		 SAR440340 300 mg versus Placebo
    Statistical analysis description
    Odds ratio, 95% CI, and p-value derived from logistic regression with treatment, baseline eosinophil strata, region, background ICS dose level at randomisation and number of exacerbation events (defined as required use of systemic [oral and/or parenteral] steroid treatment, or required hospitalisation or emergency room visit) within 1 year prior to screening.
    Comparison groups
    SAR440340 300 mg v Placebo
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0214
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.423
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.203
         upper limit
    		 0.88
    Statistical analysis title
    		 SAR440340+Dupilumab versus Placebo
    Statistical analysis description
    Odds ratio, 95% CI, and p-value derived from logistic regression with treatment, baseline eosinophil strata, region, background ICS dose level at randomisation and number of exacerbation events (defined as required use of systemic [oral and/or parenteral] steroid treatment, or required hospitalisation or emergency room visit) within 1 year prior to screening.
    Comparison groups
    SAR440340 + Dupilumab v Placebo
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0709
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.256
         upper limit
    		 1.057

    Secondary: Change From Baseline at Week 12 in Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1)

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    End point title
    		 Change From Baseline at Week 12 in Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1)
    End point description
    FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer. Pre-bronchodilator FEV1 refers to the spirometry performed after a wash period of bronchodilators (i.e., not earlier than 6 hours) after the last dose of albuterol/salbutamol or levalbuterol/levosalbutamol from a primed meter dose inhaler and withholding the last dose of LABA for at least 12 hours, and prior to administration of study drug. Analysis was performed on mITT population. Here, “number of subjects analysed” signifies subjects with available data for this end-point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo SAR440340 300 mg SAR440340 + Dupilumab Dupilumab 300 mg
    Number of subjects analysed
    41
    58
    49
    56
    Units: litres
        arithmetic mean (standard deviation)
    0.06 ( 0.35 )
    0.11 ( 0.34 )
    0.06 ( 0.37 )
    0.14 ( 0.43 )
    No statistical analyses for this end point

    Secondary: Change From Baseline at Week 12 in Post-bronchodilator Forced Expiratory Volume in 1 Second

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    End point title
    		 Change From Baseline at Week 12 in Post-bronchodilator Forced Expiratory Volume in 1 Second
    End point description
    FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer. Post-bronchodilator FEV1 refers to the spirometry performed within 30 minutes after administration of bronchodilator. Analysis was performed on mITT population. Here, “number of subjects analysed” signifies subjects with available data for this end-point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo SAR440340 300 mg SAR440340 + Dupilumab Dupilumab 300 mg
    Number of subjects analysed
    42
    58
    51
    57
    Units: litres
        arithmetic mean (standard deviation)
    -0.02 ( 0.27 )
    -0.00 ( 0.33 )
    0.06 ( 0.41 )
    0.09 ( 0.42 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first administration of IMP up to the final visit (Week 32) regardless of seriousness or relationship to IMP
    Adverse event reporting additional description
    Analysis was performed on safety population that included all enrolled subjects who had received at least 1 dose of study drug, analysed as per actual treatment received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received 2 SC injections of SAR440340 placebo along with 1 SC injection of dupilumab placebo Q2W for 12 weeks.

    Reporting group title
    SAR440340 300 mg
    Reporting group description
    		 Subjects received 2 injections of SAR440340 300 mg along with 1 injection of dupilumab placebo, SC Q2W for 12 weeks.

    Reporting group title
    SAR440340 + Dupilumab
    Reporting group description
    		 Subjects received 2 injections of SAR440340 300 mg along with 1 injection of dupilumab 300 mg, SC Q2W for 12 weeks.

    Reporting group title
    Dupilumab 300 mg
    Reporting group description
    		 Subjects received 1 injection of dupilumab 300 mg along with 2 injections of SAR440340 placebo, SC Q2W for 12 weeks.

    Serious adverse events
    		 Placebo SAR440340 300 mg SAR440340 + Dupilumab Dupilumab 300 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 74 (4.05%)
    3 / 73 (4.11%)
    2 / 74 (2.70%)
    3 / 74 (4.05%)
         number of deaths (all causes)
    0
    0
    0
    1
         number of deaths resulting from adverse events
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Alcohol Poisoning
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Vascular disorders
    Aortic Aneurysm
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep Vein Thrombosis
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Aortic Valve Incompetence
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Vascular Encephalopathy
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute Respiratory Failure
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasal Polyps
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis Acute
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess Jaw
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 73 (0.00%)
    0 / 74 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis Acute
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 73 (0.00%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         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 SAR440340 300 mg SAR440340 + Dupilumab Dupilumab 300 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    31 / 74 (41.89%)
    29 / 73 (39.73%)
    26 / 74 (35.14%)
    28 / 74 (37.84%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    7 / 74 (9.46%)
    6 / 73 (8.22%)
    5 / 74 (6.76%)
    10 / 74 (13.51%)
         occurrences all number
    7
    7
    9
    12
    General disorders and administration site conditions
    Injection Site Reaction
         subjects affected / exposed
    4 / 74 (5.41%)
    1 / 73 (1.37%)
    5 / 74 (6.76%)
    4 / 74 (5.41%)
         occurrences all number
    6
    1
    16
    4
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 74 (2.70%)
    4 / 73 (5.48%)
    2 / 74 (2.70%)
    1 / 74 (1.35%)
         occurrences all number
    4
    4
    2
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 74 (6.76%)
    1 / 73 (1.37%)
    0 / 74 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    5
    1
    0
    1
    Rhinitis Allergic
         subjects affected / exposed
    1 / 74 (1.35%)
    3 / 73 (4.11%)
    0 / 74 (0.00%)
    5 / 74 (6.76%)
         occurrences all number
    1
    4
    0
    6
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    1 / 74 (1.35%)
    4 / 73 (5.48%)
    2 / 74 (2.70%)
    3 / 74 (4.05%)
         occurrences all number
    1
    4
    2
    3
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    9 / 74 (12.16%)
    13 / 73 (17.81%)
    8 / 74 (10.81%)
    9 / 74 (12.16%)
         occurrences all number
    10
    15
    8
    11
    Upper Respiratory Tract Infection Bacterial
         subjects affected / exposed
    2 / 74 (2.70%)
    1 / 73 (1.37%)
    4 / 74 (5.41%)
    2 / 74 (2.70%)
         occurrences all number
    2
    1
    4
    2
    Urinary Tract Infection
         subjects affected / exposed
    2 / 74 (2.70%)
    1 / 73 (1.37%)
    5 / 74 (6.76%)
    3 / 74 (4.05%)
         occurrences all number
    3
    1
    7
    3
    Viral Upper Respiratory Tract Infection
         subjects affected / exposed
    5 / 74 (6.76%)
    3 / 73 (4.11%)
    5 / 74 (6.76%)
    2 / 74 (2.70%)
         occurrences all number
    6
    3
    7
    3

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Sep 2018
    1. Clarified that the safety population was analysed based on the actual treatment received and not the treatment group allocated by randomisation. 2. Added baseline background ICS dose level and number of exacerbation events within 1 year prior to screening as covariates in the logistic regression model. 3. Clarified that the responsibility of the data monitoring committee was to evaluate all study data (i.e., not limited to safety data). 4. Clarified that half of the subjects enrolled were to be on a medium dose of ICS and half on a high ICS dose, in order to have a broad representation of background therapy in the study. 5. Excluded subjects diagnosed with pulmonary or systemic disease associated with elevated peripheral eosinophil counts, eg, eosinophilic granulomatosis with polyangiitis. 6. Excluded subjects who had been treated with commercially available dupilumab. 7. Excluded subjects with known allergy to doxycycline or related compounds, or a known allergy to SAR440340 excipients. 8. Allowed samples collected for pharmacokinetics at Week 4 to be used for anti-drug antibodies (ADA) (anti-SAR440340 or anti-dupilumab antibodies) analysis, when ADA samples tests were positive at Week 12 or at the first post-treatment time point analysed. 9. Removed intra-articular steroids from permitted concomitant therapy. 10. Clarified that serum (not plasma) was collected for testing pulmonary and activation-regulated chemokine. 11. Modified the definition of overdose with non-investigational medicinal product (NIMP) to “An overdose (accidental or intentional) with any NIMP is an event suspected by the Investigator or spontaneously notified by the subject and defined as at least twice the maximum daily dose as specified in a drug label, within the intended therapeutic interval”.

    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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