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    Clinical Trial Results:
    A Double-Blind, Placebo-Controlled, Phase 2a Study to Assess the Safety, Tolerability, and Efficacy of ION-827359 in Patients with Mild to Moderate COPD with Chronic Bronchitis

    Summary
    EudraCT number
    		 2020-000210-15
    Trial protocol
    		 GB   DE   HU   CZ   PL   IT  
    Global end of trial date
    09 Aug 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Jan 2023
    First version publication date
    05 Jan 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ION-827359-CS2
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04441788
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ionis Pharmaceuticals, Inc.
    Sponsor organisation address
    2855 Gazelle Court, Carlsbad, CA, United States,
    Public contact
    Ionis Clinical Trial, Ionis Pharmaceuticals, Inc., +1 760 603 3890, ClinicalTrials@ionisph.com
    Scientific contact
    Ionis Clinical Trial, Ionis Pharmaceuticals, Inc., +1 760 603 3890, ClinicalTrials@ionisph.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
    09 Aug 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Aug 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The purpose of this study was to evaluate the effect of ION-827359 on forced expiratory volume in 1 second (FEV1) in subjects with mild to moderate chronic obstructive pulmonary disease (COPD) with chronic bronchitis (CB).
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Dec 2020
    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: 5
    Country: Number of subjects enrolled
    Czechia: 5
    Country: Number of subjects enrolled
    Germany: 45
    Country: Number of subjects enrolled
    Hungary: 5
    Worldwide total number of subjects
    60
    EEA total number of subjects
    55
    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)
    40
    From 65 to 84 years
    20
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 60 subjects were randomised at 11 study centres in Czech Republic, Germany, Hungary and the United Kingdom.

    Pre-assignment
    Screening details
    		 Of the 60 randomised subjects, one was randomised but did not receive study treatment as the subject was ineligible. The study included an 8-week screening period (including a diet-stabilisation period), a 52-week treatment period, and a 13-week post-treatment evaluation period.

    Pre-assignment period milestones
    Number of subjects started
    		 60
    Number of subjects completed
    		 59

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Ineligibility: 1
    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
    		 Placebo
    Arm description
    		 Single-dose of placebo was administered by oral inhalation via nebuliser, once every week for up to 13 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo was administered once weekly for 13 weeks.

    Arm title
    		 ION-827359 37.5 milligrams (mg)
    Arm description
    		 Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebuliser, once every week for up to 13 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ION-827359
    Investigational medicinal product code
    Other name
    Antisense Inhibitor of Epithelial Sodium Channel (ENaCRx)
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    ION-827359 37.5 mg was administered once weekly for 13 weeks.

    Arm title
    		 ION-827359 75 mg
    Arm description
    		 Single-dose of ION-827359 75 mg was administered by oral inhalation via nebuliser, once every week for up to 13 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ION-827359
    Investigational medicinal product code
    Other name
    ENaCRx
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    ION-827359 75 mg was administered once weekly for 13 weeks.

    Number of subjects in period 1 [1]
    		Placebo ION-827359 37.5 milligrams (mg) ION-827359 75 mg
    Started
    19
    21
    19
    Completed
    17
    20
    18
    Not completed
    2
    1
    1
         Voluntary Withdrawal
    1
    1
    -
         Reason not specified
    1
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Of the 60 randomised subjects, one was randomised but did not receive study treatment due to ineligibility.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Single-dose of placebo was administered by oral inhalation via nebuliser, once every week for up to 13 weeks.

    Reporting group title
    ION-827359 37.5 milligrams (mg)
    Reporting group description
    		 Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebuliser, once every week for up to 13 weeks.

    Reporting group title
    ION-827359 75 mg
    Reporting group description
    		 Single-dose of ION-827359 75 mg was administered by oral inhalation via nebuliser, once every week for up to 13 weeks.

    Reporting group values
    		 Placebo ION-827359 37.5 milligrams (mg) ION-827359 75 mg Total
    Number of subjects
    		 19 21 19 59
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.3 ( 4.54 ) 61.8 ( 5.86 ) 61.8 ( 5.39 ) -
    Gender categorical
    Units: Subjects
        Female
    		 9 7 5 21
        Male
    		 10 14 14 38
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    		 19 21 19 59
    Race
    Units: Subjects
        White
    		 19 21 18 58
        More than one race
    		 0 0 1 1
    Forced Expiratory Volume in 1 second (FEV1)
    FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation.
    Units: litres
        arithmetic mean (standard deviation)
    		 1.8317 ( 0.4670 ) 1.9311 ( 0.6608 ) 1.6536 ( 0.3498 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Single-dose of placebo was administered by oral inhalation via nebuliser, once every week for up to 13 weeks.

    Reporting group title
    ION-827359 37.5 milligrams (mg)
    Reporting group description
    		 Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebuliser, once every week for up to 13 weeks.

    Reporting group title
    ION-827359 75 mg
    Reporting group description
    		 Single-dose of ION-827359 75 mg was administered by oral inhalation via nebuliser, once every week for up to 13 weeks.

    Primary: Change From Baseline to the Primary Time Point in Forced Expiratory Volume in 1 Second (FEV1) Compared to Placebo

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    End point title
    		 Change From Baseline to the Primary Time Point in Forced Expiratory Volume in 1 Second (FEV1) Compared to Placebo [1]
    End point description
    FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. Baseline was defined as the last non-missing measurement prior to the first study drug administration. The primary time point was defined as the average of Weeks 13 and 14. The change to the primary time point was calculated as the average values of assessments at Weeks 13 and 14. Full Analysis Set (FAS) included all randomised subjects who received at least 1 dose of study drug (ION‑827359 or placebo) and who had at least 1 post-Baseline efficacy assessment (i.e., post-Baseline FEV1 assessment, Exacerbations of Chronic pulmonary Disease Tool [EXACT] Respiratory Symptoms (E-RS) score, Chronic Obstructive Pulmonary Disease [COPD] Assessment Test (CAT) score, or St. George’s Respiratory Questionnaire - COPD Specific (SGRQ-C score), post-bronchodilator FEV1 assessment. Number of subjects analysed is the number of subjects with data available for analyses in this end point.
    End point type
    Primary
    End point timeframe
    Baseline, Weeks 13 and 14
    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: Only descriptive statistics were planned to be reported for this end point.
    End point values
    		 Placebo ION-827359 37.5 milligrams (mg) ION-827359 75 mg
    Number of subjects analysed
    5
    5
    4
    Units: litres
        arithmetic mean (standard deviation)
    0.0642 ( 0.2506 )
    -0.0240 ( 0.3581 )
    0.1336 ( 0.1087 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Exacerbations of Chronic Pulmonary Disease Tool [EXACT] Respiratory Symptoms (E-RS) Daily Symptom Diary Total Score to the Primary Time Point

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    End point title
    		 Change From Baseline in the Exacerbations of Chronic Pulmonary Disease Tool [EXACT] Respiratory Symptoms (E-RS) Daily Symptom Diary Total Score to the Primary Time Point
    End point description
    The E-RS scale is a patient-reported outcome (PRO) designed to measure the symptoms of subjects with chronic obstructive pulmonary disease (COPD). It utilizes 11 respiratory symptom items from the 14-item EXACT, which measures symptoms of exacerbation. The E-RS total score quantifies respiratory symptom severity, and 3 domains assess breathlessness (comprised of 5 items, score range [0-17]), cough and sputum (comprised of 3 items, score range [0-11]), and chest symptoms (comprised of 3 items, score range [0-12]). The total score was derived by summing the 11-item scores and ranged between 0-40 with higher values indicating severe respiratory symptoms. The primary time point was defined as the average of Weeks 13 and 14. The change to the primary time point was calculated as the average values of assessments at Weeks 13 and 14. FAS population was used in this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 13 and 14
    End point values
    		 Placebo ION-827359 37.5 milligrams (mg) ION-827359 75 mg
    Number of subjects analysed
    4
    5
    4
    Units: score on a scale
        arithmetic mean (standard deviation)
    -1.08 ( 1.171 )
    -1.41 ( 2.486 )
    -1.99 ( 4.217 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Chronic Obstructive Pulmonary Disease [COPD] Assessment Test (CAT) to the Week 14 Time Point

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    End point title
    		 Change From Baseline in the Chronic Obstructive Pulmonary Disease [COPD] Assessment Test (CAT) to the Week 14 Time Point
    End point description
    The CAT is an eight-item questionnaire that will be completed by the subject and is designed to quantify the impact of COPD symptoms on the health status of subjects. Each item is rated on a 6-point scale ranging from 0 (no impairment) to 5 (maximum impairment). The total CAT score is calculated by summing the scores of all items and ranges from 0 to 40. Higher scores indicate a severe condition (more severe impact of COPD on a subject’s life). FAS included all randomised subjects who received at least 1 dose of study drug (ION‑827359 or placebo) and who had at least 1 post-Baseline efficacy assessment (i.e., post-Baseline FEV1 assessment, E-RS score, CAT score, or SGRQ-C score). Number of subjects analysed is the number of subjects with data available for analyses in this end point.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 14
    End point values
    		 Placebo ION-827359 37.5 milligrams (mg) ION-827359 75 mg
    Number of subjects analysed
    5
    5
    3
    Units: score on a scale
        arithmetic mean (standard deviation)
    -2.6 ( 2.51 )
    -0.6 ( 3.78 )
    0.0 ( 1.73 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in St. George’s Respiratory Questionnaire - COPD Specific (SGRQ-C) Total Score to the Week 14 Time Point

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    End point title
    		 Change From Baseline in St. George’s Respiratory Questionnaire - COPD Specific (SGRQ-C) Total Score to the Week 14 Time Point
    End point description
    The SGRQ is a subject completed, a disease-specific instrument designed to measure impact on overall health, daily life, and perceived well-being in subjects with obstructive airway disease. The shorter 40-item version (SGRQ-C) specifically for COPD subjects was used in this study. It consists of 40 items each weighted from 0 to a possible maximum of 100. Items 1-7 produced the symptoms score, 9-12 the activity score, and items 8, 10, 11, 13 and 14 the impacts score. Higher scores indicated a worse outcome (more limitations). FAS included all randomised subjects who received at least 1 dose of study drug (ION‑827359 or placebo) and who had at least 1 post-Baseline efficacy assessment (i.e., post-Baseline FEV1 assessment, E-RS score, CAT score, or SGRQ-C score). Number of subjects analysed is the number of subjects with data available for analyses in this end point.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 14
    End point values
    		 Placebo ION-827359 37.5 milligrams (mg) ION-827359 75 mg
    Number of subjects analysed
    5
    5
    3
    Units: score on a scale
        arithmetic mean (standard deviation)
    -15.93 ( 19.515 )
    -1.74 ( 3.839 )
    -0.76 ( 2.350 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Post-Bronchodilator FEV1

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    End point title
    		 Change From Baseline in Post-Bronchodilator FEV1
    End point description
    Post-bronchodilator FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation after administration of bronchodilator. Baseline was defined as the last non-missing measurement prior to the first study drug administration. FAS included all randomised subjects who received at least 1 dose of study drug (ION‑827359 or placebo) and who had at least 1 post-Baseline efficacy assessment (i.e., post-Baseline FEV1 assessment, E-RS score, CAT score, or SGRQ-C score). Number of subjects analysed is the number of subjects with data available for analyses in this end point.
    End point type
    Secondary
    End point timeframe
    From Baseline to end of treatment (EOT) [Up to Week 14]
    End point values
    		 Placebo ION-827359 37.5 milligrams (mg) ION-827359 75 mg
    Number of subjects analysed
    3
    5
    3
    Units: litres
        arithmetic mean (standard deviation)
    0.0663 ( 0.0685 )
    0.0320 ( 0.2379 )
    0.1180 ( 0.1006 )
    No statistical analyses for this end point

    Secondary: Cmax: Maximum Observed Plasma Concentration for ION-827359

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    End point title
    		 Cmax: Maximum Observed Plasma Concentration for ION-827359 [2]
    End point description
    PK population included all subjects who were randomised and received at least 1 dose of active study drug (ION-827359) and had at least 1 evaluable PK sample collected and analysed with reportable result. n=number of subjects with data available for analysis at the specified time point. 99999 denotes that the geometric coefficient of variation was not estimable due to lower number of subjects.
    End point type
    Secondary
    End point timeframe
    Days 1 and 85
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This end point was planned to be analysed only in the ION-827359 37.5 mg and ION-827359 75 mg reporting groups.
    End point values
    		 ION-827359 37.5 milligrams (mg) ION-827359 75 mg
    Number of subjects analysed
    6
    6
    Units: nanogram per millilitre (ng/mL)
    geometric mean (geometric coefficient of variation)
        Day 1 (n=6,6)
    85.6 ( 198 )
    203 ( 52.6 )
        Day 85 (n=1,2)
    53.5 ( 99999 )
    195 ( 124 )
    No statistical analyses for this end point

    Secondary: Tmax: Time to Reach the Maximum Plasma Concentration for ION-827359

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    End point title
    		 Tmax: Time to Reach the Maximum Plasma Concentration for ION-827359 [3]
    End point description
    PK population included all subjects who were randomised and received at least 1 dose of active study drug (ION-827359) and had at least 1 evaluable PK sample collected and analysed with reportable result. n=number of subjects with data available for analysis at the specified time point.
    End point type
    Secondary
    End point timeframe
    Days 1 and 85
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This end point was planned to be analysed only in the ION-827359 37.5 mg and ION-827359 75 mg reporting groups.
    End point values
    		 ION-827359 37.5 milligrams (mg) ION-827359 75 mg
    Number of subjects analysed
    6
    6
    Units: hours
    median (full range (min-max))
        Day 1 (n=6,6)
    1.54 (0.567 to 2.05)
    1.64 (0.667 to 2.12)
        Day 85 (n=1,2)
    1.98 (1.98 to 1.98)
    3.11 (1.73 to 4.48)
    No statistical analyses for this end point

    Secondary: AUC[0-24h]: Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours for ION-827359

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    End point title
    		 AUC[0-24h]: Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours for ION-827359 [4]
    End point description
    PK population included all subjects who were randomised and received at least 1 dose of active study drug (ION-827359) and had at least 1 evaluable PK sample collected and analysed with reportable result. n=number of subjects with data available for analysis at the specified time point. 99999 denotes that the geometric coefficient of variation was not estimable due to lower number of subjects.
    End point type
    Secondary
    End point timeframe
    Days 1 and 85
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This end point was planned to be analysed only in the ION-827359 37.5 mg and ION-827359 75 mg reporting groups.
    End point values
    		 ION-827359 37.5 milligrams (mg) ION-827359 75 mg
    Number of subjects analysed
    6
    6
    Units: hours*nanogram per millilitre (h*ng/mL)
    geometric mean (geometric coefficient of variation)
        Day 1 (n=6,6)
    528 ( 190 )
    1323 ( 66.0 )
        Day 85 (n=1,2)
    312 ( 99999 )
    2416 ( 252 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With at Least One Treatment-Emergent Adverse Event (TEAE) Based on Severity

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    End point title
    		 Percentage of Subjects With at Least One Treatment-Emergent Adverse Event (TEAE) Based on Severity
    End point description
    An adverse event (AE) can be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of medicinal (investigational) product, whether or not the AE is considered related to the medicinal (investigational) product. A TEAE is defined as any AE starting or getting worse on or after the first dose of the study drug. The severity of a TEAE was assessed by the investigator and classified into one of the following: mild, moderate, and severe. Safety population included all subjects who were randomised and received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Up to Week 24
    End point values
    		 Placebo ION-827359 37.5 milligrams (mg) ION-827359 75 mg
    Number of subjects analysed
    19
    21
    19
    Units: percentage of subjects
    number (not applicable)
        Mild
    10.5
    14.3
    15.8
        Moderate
    52.6
    38.1
    63.2
        Severe
    10.5
    0
    5.3
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Clinically Significant Change in Laboratory Values

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    End point title
    		 Percentage of Subjects With Clinically Significant Change in Laboratory Values
    End point description
    Laboratory parameters for serum chemistry, haematology, urinalysis, coagulation, complement, and lipids were assessed. Safety population included all subjects who are were randomised and received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Up to Week 24
    End point values
    		 Placebo ION-827359 37.5 milligrams (mg) ION-827359 75 mg
    Number of subjects analysed
    19
    21
    19
    Units: percentage of subjects
        number (not applicable)
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Clinically Significant Change in Vital Signs

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    End point title
    		 Percentage of Subjects With Clinically Significant Change in Vital Signs
    End point description
    Vital signs included assessment of heart rate, blood pressure, respiratory rate, and temperature. Safety population included all subjects who were randomised and received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Up to Week 24
    End point values
    		 Placebo ION-827359 37.5 milligrams (mg) ION-827359 75 mg
    Number of subjects analysed
    19
    21
    19
    Units: percentage of subjects
        number (not applicable)
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Clinically Significant Change in Electrocardiogram (ECG) Findings

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    End point title
    		 Percentage of Subjects With Clinically Significant Change in Electrocardiogram (ECG) Findings
    End point description
    ECG parameters of ventricular rate, PR interval, QRS duration, QT, or QTc were assessed. Safety population included all subjects who were randomised and received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Up to Week 24
    End point values
    		 Placebo ION-827359 37.5 milligrams (mg) ION-827359 75 mg
    Number of subjects analysed
    19
    21
    19
    Units: percentage of subjects
        number (not applicable)
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Week 24
    Adverse event reporting additional description
    Safety population included all subjects who are were randomised and received at least 1 dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Single-dose of placebo was administered by oral inhalation via nebuliser, once every week for up to 13 weeks

    Reporting group title
    ION-827359 37.5 mg
    Reporting group description
    		 Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebuliser, once every week for up to 13 weeks.

    Reporting group title
    ION-827359 75 mg
    Reporting group description
    		 Single-dose of ION-827359 75 mg was administered by oral inhalation via nebuliser, once every week for up to 13 weeks.

    Serious adverse events
    		 Placebo ION-827359 37.5 mg ION-827359 75 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 21 (4.76%)
    1 / 19 (5.26%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 21 (4.76%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo ION-827359 37.5 mg ION-827359 75 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 19 (73.68%)
    8 / 21 (38.10%)
    16 / 19 (84.21%)
    Vascular disorders
    Arteriosclerosis
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Peripheral vascular disorder
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Burning sensation
         subjects affected / exposed
    0 / 19 (0.00%)
    2 / 21 (9.52%)
    0 / 19 (0.00%)
         occurrences all number
    0
    6
    0
    Chest discomfort
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Cyst
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Pyrexia
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Immune system disorders
    Vaccination complication
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Sputum increased
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    4
    Cough
         subjects affected / exposed
    1 / 19 (5.26%)
    5 / 21 (23.81%)
    7 / 19 (36.84%)
         occurrences all number
    1
    11
    23
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    5 / 19 (26.32%)
    0 / 21 (0.00%)
    4 / 19 (21.05%)
         occurrences all number
    6
    0
    5
    Dyspnoea
         subjects affected / exposed
    0 / 19 (0.00%)
    2 / 21 (9.52%)
    5 / 19 (26.32%)
         occurrences all number
    0
    4
    5
    Chest pain
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Throat irritation
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    5
    0
    0
    Bronchial irritation
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Bronchospasm
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Dysphonia
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Nasal congestion
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Rhinitis
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    3
    Rhinorrhoea
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Sputum discoloured
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Product issues
    Product taste abnormal
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    7
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Blood glucose decreased
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    FEV1/FVC ratio decreased
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    2
    SARS-CoV-2 test positive
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Injury, poisoning and procedural complications
    Skin laceration
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Cardiac disorders
    Cyanosis
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 21 (4.76%)
    2 / 19 (10.53%)
         occurrences all number
    0
    1
    2
    Eye disorders
    Eye irritation
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 19 (10.53%)
    4 / 21 (19.05%)
    0 / 19 (0.00%)
         occurrences all number
    2
    4
    0
    Abdominal pain
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Dyspepsia
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Gastritis
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Tongue dry
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    5
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Neck pain
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 19 (15.79%)
    1 / 21 (4.76%)
    0 / 19 (0.00%)
         occurrences all number
    3
    1
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Bronchitis
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Oral candidiasis
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 May 2020
    The primary purpose of Amendment 1 was to mitigate any potential effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on study subjects and study site personnel.
    10 Aug 2020
    The primary purpose of Amendment 2 was addition of contraceptive requirements in the United Kingdom.
    02 Feb 2021
    The primary purpose of Amendment 3 was to help prevent any potential bronchospasm after inhalation of study drug.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    09 Aug 2021
    The study was terminated based on the toxicology findings from a 9-month study and subjects who had not completed the treatment period were instructed to terminate dosing and return for an end of study visit, followed by the 10-week follow-up period.
    -

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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