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    Clinical Trial Results:
    Placebo-Controlled Proof of Concept Study to Investigate ANB020 Activity in Adult Patients with Severe Eosinophilic Asthma

    Summary
    EudraCT number
    		 2017-000647-40
    Trial protocol
    		 GB  
    Global end of trial date
    30 Oct 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Apr 2021
    First version publication date
    16 Apr 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ANB020-004
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03469934
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AnaptysBio, Inc
    Sponsor organisation address
    10421 Pacific Center Court, Suite 200, San Diego, United States, CA 92121
    Public contact
    AnaptysBio Clinical Trials Information, AnaptysBio, Inc, +1 8583626387, clinicaltrialinfo@anaptysbio.com
    Scientific contact
    AnaptysBio Clinical Trials Information, AnaptysBio, Inc, +1 8583626387, clinicaltrialinfo@anaptysbio.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
    30 Oct 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Oct 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objectives of the study were: - To measure the reduction of eosinophils (blood eosinophil count) from Baseline (Day 1 pre-dose) to Day 22 in adult severe eosinophilic asthma patients administered with etokimab; - To assess the safety and tolerability of a single, intravenous (IV) dose of etokimab compared to placebo in adult patients with severe eosinophilic asthma.
    Protection of trial subjects
    This study was conducted in accordance with the protocol and with the following: - Consensus ethical principles derived from international guidelines including the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines; - Applicable International Conference on Harmonisation Good Clinical Practice Guidelines; - Applicable laws and regulations.
    Background therapy
    		 Patients with eosinophilic asthma with exacerbations requiring rescue medication were expected to be on bronchodilators and were required to be on high-dose inhaled corticosteroids and long-acting beta-2 agonists.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Nov 2017
    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
    United Kingdom: 9
    Country: Number of subjects enrolled
    United States: 16
    Worldwide total number of subjects
    25
    EEA total number of subjects
    0
    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)
    25
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted in adults with severe eosinophilic asthma. Patients were randomized on Day 1 to receive a single IV dose of either etokimab or placebo in a 1:1 ratio.

    Pre-assignment
    Screening details
    		 This study consisted of a screening period (7 to 14 days), treatment period, and follow-up period (total of 127 days). The total duration of the study was approximately 141 days.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Etokimab
    Arm description
    		 Etokimab 300 milligrams (mg)/100 milliliters (mL) was administered by IV infusion once on Day 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Etokimab
    Investigational medicinal product code
    ANB020
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    A single dose of 300 mg etokimab was administered on Day 1 over 1 hour by IV infusion in polyvinyl chloride or polyolefin bags following dilution to a total volume of 100 mL with 0.9% sodium chloride (NaCl).

    Arm title
    		 Placebo
    Arm description
    		 Placebo was administered by IV infusion once on Day 1.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    A single dose of 100 mL of placebo (0.9% NaCl) was administered on Day 1 over 1 hour by IV infusion.

    Number of subjects in period 1
    		Etokimab Placebo
    Started
    12
    13
    Completed
    12
    12
    Not completed
    0
    1
         Consent withdrawn by subject
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Etokimab
    Reporting group description
    		 Etokimab 300 milligrams (mg)/100 milliliters (mL) was administered by IV infusion once on Day 1.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo was administered by IV infusion once on Day 1.

    Reporting group values
    		 Etokimab Placebo Total
    Number of subjects
    		 12 13 25
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 40.6 ( 14.72 ) 36.3 ( 14.70 ) -
    Gender categorical
    Units: Subjects
        Female
    		 3 4 7
        Male
    		 9 9 18
    Race
    Units: Subjects
        Black or African American
    		 0 2 2
        White
    		 12 11 23
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    		 12 12 24
        Not reported
    		 0 1 1
    Height
    Units: centimeters
        arithmetic mean (standard deviation)
    		 175.7 ( 7.73 ) 173.9 ( 11.26 ) -
    Weight
    Units: kilograms
        arithmetic mean (standard deviation)
    		 95.0 ( 18.04 ) 79.6 ( 19.30 ) -
    Body Mass Index
    Units: kilogram/meter squared
        arithmetic mean (standard deviation)
    		 30.7 ( 4.94 ) 26.4 ( 6.00 ) -

    End points

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    End points reporting groups
    Reporting group title
    Etokimab
    Reporting group description
    		 Etokimab 300 milligrams (mg)/100 milliliters (mL) was administered by IV infusion once on Day 1.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo was administered by IV infusion once on Day 1.

    Primary: Change in Peripheral Eosinophil Count from Baseline to Day 22

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    End point title
    		 Change in Peripheral Eosinophil Count from Baseline to Day 22
    End point description
    Blood samples to determine the eosinophil count were obtained as part of the standard hematology safety laboratory panel. The Pharmacodynamic (PD) Analysis Set included all patients who received etokimab or placebo and provided at least 1 evaluable post-dose PD measurement without any events or protocol deviation deemed to affect PD assessment.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and Day 22
    End point values
    		 Etokimab Placebo
    Number of subjects analysed
    11
    13
    Units: 10^9/liter (L)
        least squares mean (confidence interval 95%)
    -0.199 (-0.351 to -0.046)
    -0.141 (-0.280 to -0.002)
    Statistical analysis title
    		 Etokimab versus (vs) Placebo
    Statistical analysis description
    Results based on a linear mixed model with fixed effects for treatment, timepoint, treatment × timepoint, and baseline value and a repeated timepoint effect within a patient under an unstructured covariance matrix.
    Comparison groups
    Etokimab v Placebo
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5703
    Method
    		 Mixed models analysis
    Parameter type
    		 Least-squares (LS) mean difference
    Point estimate
    -0.058
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.265
         upper limit
    		 0.15

    Primary: Number of Patients who Experienced an Adverse Event (AE)

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    End point title
    		 Number of Patients who Experienced an Adverse Event (AE) [1]
    End point description
    An AE is any untoward medical occurrence in a patient or clinical investigation patient administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. A treatment-emergent AE (TEAE) is an AE that started or worsened in severity on or after the date and time of the study drug infusion. A serious adverse event (SAE), experience or reaction, is any untoward medical occurrence (whether considered to be related to the study drug or not) that at any dose: - Results in death; - Is life-threatening; - Requires inpatient hospitalization or prolongation of existing hospitalization; - Results in persistent or significant disability/incapacity; - Is a congenital anomaly/birth defect; - Other medically important event. The Safety Analysis Set included all patients who received etokimab or placebo.
    End point type
    Primary
    End point timeframe
    Day 1 to Day 127
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 Etokimab Placebo
    Number of subjects analysed
    12
    13
    Units: patients
        Any non-TEAEs
    1
    0
        Any TEAEs
    6
    5
        Any SAEs
    0
    0
        Any TEAEs leading to withdrawal from the study
    0
    0
    No statistical analyses for this end point

    Primary: Number of Patients with Clinically Meaningful Findings in Physical Examination Assessments

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    End point title
    		 Number of Patients with Clinically Meaningful Findings in Physical Examination Assessments [2]
    End point description
    The physical examination included evaluation of general appearance, head, eyes, ears, nose, and throat, and the pulmonary, cardiovascular, gastrointestinal, renal/genitourological, endocrine (including thyroid), musculoskeletal/spinal, lymphatic, and dermatologic systems. The Safety Analysis Set included all patients who received etokimab or placebo.
    End point type
    Primary
    End point timeframe
    Day 1 to Day 127
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 Etokimab Placebo
    Number of subjects analysed
    12
    13
    Units: patients
    0
    0
    No statistical analyses for this end point

    Primary: Number of Patients with Clinically Meaningful Findings in Vital Signs Measurements

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    End point title
    		 Number of Patients with Clinically Meaningful Findings in Vital Signs Measurements [3]
    End point description
    Vital signs included pulse rate, respiratory rate, body temperature, systolic blood pressure (BP), and diastolic BP. The Safety Analysis Set included all patients who received etokimab or placebo.
    End point type
    Primary
    End point timeframe
    Day 1 to Day 127
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 Etokimab Placebo
    Number of subjects analysed
    12
    13
    Units: patients
    0
    0
    No statistical analyses for this end point

    Primary: Number of Patients with Clinically Meaningful Findings in Clinical Safety Laboratory Evaluations

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    End point title
    		 Number of Patients with Clinically Meaningful Findings in Clinical Safety Laboratory Evaluations [4]
    End point description
    Hematology, clinical chemistry, virology, urinalysis, and drugs of abuse testing was performed. The clinical laboratory test results were reviewed for potential clinical significance, based on Investigator’s discretion throughout the study. The Investigator evaluated any change in laboratory values. If the Investigator determined a laboratory abnormality to be clinically significant, it was considered a laboratory AE; however, if the abnormal laboratory value was consistent with a current diagnosis, it was documented accordingly. The Safety Analysis Set included all patients who received etokimab or placebo.
    End point type
    Primary
    End point timeframe
    Day 1 to Day 127
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 Etokimab Placebo
    Number of subjects analysed
    12
    13
    Units: patients
    0
    0
    No statistical analyses for this end point

    Primary: Number of Patients with Clinically Meaningful Findings in Electrocardiogram (ECG) Assessments

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    End point title
    		 Number of Patients with Clinically Meaningful Findings in Electrocardiogram (ECG) Assessments [5]
    End point description
    A standard 12-lead ECG was performed by a qualified physician or nurse. The following parameters were documented: heart rate, PR interval, QRS interval, QT interval, and QTc interval. The Safety Analysis Set included all patients who received etokimab or placebo.
    End point type
    Primary
    End point timeframe
    Day 1 to Day 127
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 Etokimab Placebo
    Number of subjects analysed
    12
    13
    Units: patients
    0
    0
    No statistical analyses for this end point

    Primary: Number of Asthma Exacerbations

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    End point title
    		 Number of Asthma Exacerbations [6]
    End point description
    The definition of asthma exacerbation for this endpoint included: - Use of systemic corticosteroids (or a temporary increase in a stable oral corticosteroid background dose) for at least 3 days; a single depo-injectable dose of corticosteroids was considered equivalent to a 3-day course of systemic corticosteroids; or - An emergency room/urgent care visit (defined as evaluation and treatment for <24 hours in an emergency department or urgent care center) due to asthma that required systemic corticosteroids (as per above); or - An inpatient hospitalization (defined as admission to an inpatient facility and/or evaluation and treatment in a healthcare facility for ≥24 hours due to asthma). The Full Analysis Set included all patients who received etokimab or placebo and had at least 1 post-baseline blood eosinophils count assessment (Day 2).
    End point type
    Primary
    End point timeframe
    Day 1 to Day 127
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 Etokimab Placebo
    Number of subjects analysed
    12
    13
    Units: exacerbations
    1
    1
    No statistical analyses for this end point

    Primary: Number of Patients with Anti-drug Antibodies (ADA)

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    End point title
    		 Number of Patients with Anti-drug Antibodies (ADA) [7]
    End point description
    Number of patients with positive ADA assay result is reported. The Safety Analysis Set included all patients who received etokimab or placebo.
    End point type
    Primary
    End point timeframe
    Day 1 pre-dose and Days 8, 36, 85, 106 and 127
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 Etokimab Placebo
    Number of subjects analysed
    12
    13
    Units: patients
        Day 1 (n = 12, 13)
    1
    1
        Day 8 (n = 12, 13)
    0
    2
        Day 36 (n = 12, 13)
    0
    2
        Day 85 (n = 12, 13)
    1
    1
        Day 106 (n = 12, 12)
    1
    1
        Day 127 (n = 12, 12)
    2
    1
    No statistical analyses for this end point

    Secondary: Change in Peripheral Eosinophil Count from Baseline to Day 127

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    End point title
    		 Change in Peripheral Eosinophil Count from Baseline to Day 127
    End point description
    Blood samples to determine the eosinophil count were obtained as part of the standard hematology safety laboratory panel. The PD Analysis Set included all patients who received etokimab or placebo and provided at least 1 evaluable post-dose PD measurement without any events or protocol deviation deemed to affect PD assessment.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Day 127
    End point values
    		 Etokimab Placebo
    Number of subjects analysed
    12
    13
    Units: 10^9/L
        least squares mean (confidence interval 95%)
    -0.194 (-0.330 to -0.058)
    -0.144 (-0.275 to -0.014)
    Statistical analysis title
    		 Etokimab vs Placebo
    Statistical analysis description
    Results based on a linear mixed model with fixed effects for treatment, timepoint, treatment × timepoint, and baseline value and a repeated timepoint effect within a patient under an unstructured covariance matrix.
    Comparison groups
    Etokimab v Placebo
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5901
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.239
         upper limit
    		 0.139

    Secondary: Change in Forced Expiratory Volume in 1 Second from Baseline to Day 127

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    End point title
    		 Change in Forced Expiratory Volume in 1 Second from Baseline to Day 127
    End point description
    Spirometry was performed according to the American Thoracic Society/European Respiratory Society guidelines (ATS/ERS). Pre-bronchodilator spirometry was performed after appropriate bronchodilator withholding period in the morning. Forced expiratory maneuvers were performed with the patient seated in an upright position if possible. Three acceptable maneuvers were obtained for each test. The Full Analysis Set included all patients who received etokimab or placebo and had at least 1 post-baseline blood eosinophils count assessment (Day 2).
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Day 127
    End point values
    		 Etokimab Placebo
    Number of subjects analysed
    12
    12
    Units: liters
        least squares mean (standard error)
    0.27 ( 0.116 )
    0.18 ( 0.116 )
    Statistical analysis title
    		 Etokimab vs Placebo
    Statistical analysis description
    P-value was obtained using analysis of covariance (ANCOVA) model with treatment as fixed effect and baseline result as covariate.
    Comparison groups
    Etokimab v Placebo
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.596
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.25
         upper limit
    		 0.43
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.164

    Secondary: Change in Fractional Exhaled Nitric Oxide (FeNO) from Baseline to Day 127

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    End point title
    		 Change in Fractional Exhaled Nitric Oxide (FeNO) from Baseline to Day 127
    End point description
    Measurement of FeNO was performed in accordance with the guidelines published by ATS/ERS. The FeNO test was performed before the spirometry testing. The Full Analysis Set included all patients who received etokimab or placebo and had at least 1 post-baseline blood eosinophils count assessment (Day 2).
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Day 127
    End point values
    		 Etokimab Placebo
    Number of subjects analysed
    12
    12
    Units: parts per billion
        least squares mean (standard error)
    2.10 ( 6.580 )
    -0.43 ( 6.580 )
    Statistical analysis title
    		 Etokimab vs Placebo
    Statistical analysis description
    P-value is obtained using ANCOVA model with treatment as fixed effect and baseline result as covariate.
    Comparison groups
    Etokimab v Placebo
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7993
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    2.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.9
         upper limit
    		 22.96
    Variability estimate
    Standard error of the mean
    Dispersion value
    9.823

    Secondary: Whole Blood Ex-vivo Induced Interferon-Gamma (IFN-γ) Levels (United Kingdom [UK] Sites Only)

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    End point title
    		 Whole Blood Ex-vivo Induced Interferon-Gamma (IFN-γ) Levels (United Kingdom [UK] Sites Only)
    End point description
    Blood samples for ex-vivo induced IFN-γ assessment were collected in a sodium heparin tube and the measurement of ex-vivo induced IFN-γ was performed using validated assay methods. The PD Analysis Set included all patients who received etokimab or placebo and provided at least 1 evaluable post-dose PD measurement without any events or protocol deviation deemed to affect PD assessment. Only patients randomized within the UK were included. 9999 = below the lower limit of quantification; 99999 = not determined; 999999 = no patients were analyzed at that specific timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Days 8, 36, 85, 106 and 127
    End point values
    		 Etokimab Placebo
    Number of subjects analysed
    4
    5
    Units: nanograms/L
    arithmetic mean (standard deviation)
        Day 1 (n = 4, 4)
    702.215 ( 581.947 )
    2490.575 ( 3577.893 )
        Day 8 (n = 3, 2)
    9999 ( 99999 )
    99999 ( 99999 )
        Day 36 (n = 2, 3)
    99999 ( 99999 )
    8208.247 ( 4012.238 )
        Day 85 (n = 2, 1)
    99999 ( 99999 )
    99999 ( 99999 )
        Day 106 (n = 2, 0)
    99999 ( 99999 )
    999999 ( 999999 )
        Day 127 (n = 4, 5)
    1103.323 ( 1086.280 )
    7308.442 ( 8458.639 )
    No statistical analyses for this end point

    Secondary: Maximum Observed Concentration (Cmax) of Etokimab

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    End point title
    		 Maximum Observed Concentration (Cmax) of Etokimab [8]
    End point description
    Cmax was derived using non-compartmental methods. The PK Analysis Set included all patients who received etokimab and had at least 1 post-dose serum concentration data available for etokimab without any events or protocol deviation deemed to affect PK assessments.
    End point type
    Secondary
    End point timeframe
    Day 1 pre-dose, 0.5 hours post-start of infusion, end of infusion (EOI), EOI + 3 hours, EOI + 6 hours, and Days 2, 8, 22, 36 and 64
    Notes
    [8] - 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: PK assessment was pre-specified for the etokimab arm only.
    End point values
    		 Etokimab
    Number of subjects analysed
    11
    Units: micrograms (μg)/mL
        geometric mean (geometric coefficient of variation)
    77.71 ( 24.1 )
    No statistical analyses for this end point

    Secondary: Time to Maximum Observed Concentration (Tmax) of Etokimab

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    End point title
    		 Time to Maximum Observed Concentration (Tmax) of Etokimab [9]
    End point description
    Tmax was derived using non-compartmental methods. The PK Analysis Set included all patients who received etokimab and had at least 1 post-dose serum concentration data available for etokimab without any events or protocol deviation deemed to affect PK assessments.
    End point type
    Secondary
    End point timeframe
    Day 1 pre-dose, 0.5 hours post-start of infusion, EOI, EOI + 3 hours, EOI + 6 hours, and Days 2, 8, 22, 36 and 64
    Notes
    [9] - 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: PK assessment was pre-specified for the etokimab arm only.
    End point values
    		 Etokimab
    Number of subjects analysed
    11
    Units: hours
        median (full range (min-max))
    1.020 (0.53 to 4.08)
    No statistical analyses for this end point

    Secondary: Area Under the Concentration-time Curve in Serum from Time Zero (pre-dose) Extrapolated to Infinite Time (AUC[0-inf]) of Etokimab

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    End point title
    		 Area Under the Concentration-time Curve in Serum from Time Zero (pre-dose) Extrapolated to Infinite Time (AUC[0-inf]) of Etokimab [10]
    End point description
    AUC(0-inf) was derived using non-compartmental methods. The PK Analysis Set included all patients who received etokimab and had at least 1 post-dose serum concentration data available for etokimab without any events or protocol deviation deemed to affect PK assessments.
    End point type
    Secondary
    End point timeframe
    Day 1 pre-dose, 0.5 hours post-start of infusion, EOI, EOI + 3 hours, EOI + 6 hours, and Days 2, 8, 22, 36 and 64
    Notes
    [10] - 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: PK assessment was pre-specified for the etokimab arm only.
    End point values
    		 Etokimab
    Number of subjects analysed
    11
    Units: hours (h)*μg/mL
        geometric mean (geometric coefficient of variation)
    13750 ( 32.3 )
    No statistical analyses for this end point

    Secondary: Area Under the Serum Concentration-time Curve from Time Zero to the Time of the Last Quantifiable Concentration (AUC[0-last]) of Etokimab

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    End point title
    		 Area Under the Serum Concentration-time Curve from Time Zero to the Time of the Last Quantifiable Concentration (AUC[0-last]) of Etokimab [11]
    End point description
    AUC0-last was derived using non-compartmental methods. The PK Analysis Set included all patients who received etokimab and had at least 1 post-dose serum concentration data available for etokimab without any events or protocol deviation deemed to affect PK assessments.
    End point type
    Secondary
    End point timeframe
    Day 1 pre-dose, 0.5 hours post-start of infusion, EOI, EOI + 3 hours, EOI + 6 hours, and Days 2, 8, 22, 36 and 64
    Notes
    [11] - 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: PK assessment was pre-specified for the etokimab arm only.
    End point values
    		 Etokimab
    Number of subjects analysed
    11
    Units: h*μg/mL
        geometric mean (geometric coefficient of variation)
    13050 ( 30.4 )
    No statistical analyses for this end point

    Secondary: Apparent Total Body Clearance (CL) of Etokimab

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    End point title
    		 Apparent Total Body Clearance (CL) of Etokimab [12]
    End point description
    CL was derived using non-compartmental methods. The PK Analysis Set included all patients who received etokimab and had at least 1 post-dose serum concentration data available for etokimab without any events or protocol deviation deemed to affect PK assessments.
    End point type
    Secondary
    End point timeframe
    Day 1 pre-dose, 0.5 hours post-start of infusion, EOI, EOI + 3 hours, EOI + 6 hours, and Days 2, 8, 22, 36 and 64
    Notes
    [12] - 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: PK assessment was pre-specified for the etokimab arm only.
    End point values
    		 Etokimab
    Number of subjects analysed
    11
    Units: L/h
        geometric mean (geometric coefficient of variation)
    0.02180 ( 32.4 )
    No statistical analyses for this end point

    Secondary: Apparent Terminal Rate Constant (λz) of Etokimab

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    End point title
    		 Apparent Terminal Rate Constant (λz) of Etokimab [13]
    End point description
    λz was derived using non-compartmental methods. The PK Analysis Set included all patients who received etokimab and had at least 1 post-dose serum concentration data available for etokimab without any events or protocol deviation deemed to affect PK assessments.
    End point type
    Secondary
    End point timeframe
    Day 1 pre-dose, 0.5 hours post-start of infusion, EOI, EOI + 3 hours, EOI + 6 hours, and Days 2, 8, 22, 36 and 64
    Notes
    [13] - 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: PK assessment was pre-specified for the etokimab arm only.
    End point values
    		 Etokimab
    Number of subjects analysed
    11
    Units: 1/h
        geometric mean (geometric coefficient of variation)
    0.002096 ( 29.2 )
    No statistical analyses for this end point

    Secondary: Apparent Terminal Half-life (t1/2) of Etokimab

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    End point title
    		 Apparent Terminal Half-life (t1/2) of Etokimab [14]
    End point description
    t1/2 was derived using non-compartmental methods. The PK Analysis Set included all patients who received etokimab and had at least 1 post-dose serum concentration data available for etokimab without any events or protocol deviation deemed to affect PK assessments.
    End point type
    Secondary
    End point timeframe
    Day 1 pre-dose, 0.5 hours post-start of infusion, EOI, EOI + 3 hours, EOI + 6 hours, and Days 2, 8, 22, 36 and 64
    Notes
    [14] - 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: PK assessment was pre-specified for the etokimab arm only.
    End point values
    		 Etokimab
    Number of subjects analysed
    11
    Units: hours
        geometric mean (geometric coefficient of variation)
    330.5 ( 29.2 )
    No statistical analyses for this end point

    Secondary: Volume of Distribution During Terminal Phase (Vz) of Etokimab

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    End point title
    		 Volume of Distribution During Terminal Phase (Vz) of Etokimab [15]
    End point description
    Vz was derived using non-compartmental methods. The PK Analysis Set included all patients who received etokimab and had at least 1 post-dose serum concentration data available for etokimab without any events or protocol deviation deemed to affect PK assessments.
    End point type
    Secondary
    End point timeframe
    Day 1 pre-dose, 0.5 hours post-start of infusion, EOI, EOI + 3 hours, EOI + 6 hours, and Days 2, 8, 22, 36 and 64
    Notes
    [15] - 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: PK assessment was pre-specified for the etokimab arm only.
    End point values
    		 Etokimab
    Number of subjects analysed
    11
    Units: liters
        geometric mean (geometric coefficient of variation)
    10.40 ( 19.2 )
    No statistical analyses for this end point

    Secondary: Volume of Distribution at Steady State Following IV Dosing (Vss) of Etokimab

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    End point title
    		 Volume of Distribution at Steady State Following IV Dosing (Vss) of Etokimab [16]
    End point description
    Vss was derived using non-compartmental methods. The PK Analysis Set included all patients who received etokimab and had at least 1 post-dose serum concentration data available for etokimab without any events or protocol deviation deemed to affect PK assessments.
    End point type
    Secondary
    End point timeframe
    Day 1 pre-dose, 0.5 hours post-start of infusion, EOI, EOI + 3 hours, EOI + 6 hours, and Days 2, 8, 22, 36 and 64
    Notes
    [16] - 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: PK assessment was pre-specified for the etokimab arm only.
    End point values
    		 Etokimab
    Number of subjects analysed
    11
    Units: liters
        geometric mean (geometric coefficient of variation)
    8.382 ( 16.6 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 to Day 127
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20
    Reporting groups
    Reporting group title
    Etokimab
    Reporting group description
    		 Etokimab 300 mg/100 mL was administered by IV infusion once on Day 1.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo was administered by IV infusion once on Day 1.

    Serious adverse events
    		 Etokimab Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Etokimab Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 12 (50.00%)
    5 / 13 (38.46%)
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Contusion
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Face injury
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Soft tissue injury
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 13 (15.38%)
         occurrences all number
    1
    2
    Cough
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    2
    Psychiatric disorders
    Panic attack
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Pharyngitis streptococcal
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    Pharyngitis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Sinusitis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 May 2017
    Changes encompassed by this amendment included administrative changes and updates to the inclusion criteria, patient restrictions, and blinding.
    04 Jan 2018
    Changes encompassed by this amendment included administrative changes, and updates to the synopsis, background information, discussion of study design, summary of study design, inclusion criteria, exclusion criteria, patient restrictions, patient withdrawal, excluded medications, spirometry, timing of procedures, appendix VI - IFN-y collection timepoints, and schedule of events.
    16 Feb 2018
    Changes encompassed by this amendment included updates to the inclusion criteria, method of assigning patients to treatment group, and unblinding.
    30 Oct 2018
    Amendment dated 31-Oct-2018. This amendment combined the United States and UK ANB020-004 protocols and updated the clinical study background to incorporate the most recent updates to the Investigator Brochure. No changes were made to study procedures in this amendment. Changes encompassed by this amendment included administrative changes, clinical updates, and country specific assessments combined into 1 global protocol.

    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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