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    Clinical Trial Results:
    The FLAGSHIP Study: A 12-week Phase II Study to Evaluate the Efficacy and Safety of AQX-1125 Following Exacerbations in Patients with Chronic Obstructive Pulmonary Disease (COPD) by targeting the SHIP1 Pathway

    Summary
    EudraCT number
    		 2013-001951-11
    Trial protocol
    		 SE   FI   HU   DK   PL  
    Global end of trial date
    13 Nov 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Dec 2018
    First version publication date
    08 Dec 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AQX-1125-202
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01954628
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Aquinox Pharmaceuticals (Canada) Inc.
    Sponsor organisation address
    450 - 887 Great Northern Way, Vancouver, Canada, V5T 4T5
    Public contact
    Clinical Operations, Aquinox Pharmaceuticals (Canada) Inc., +001 604 629 9223, clinical@aqxpharma.com
    Scientific contact
    Clinical Operations, Aquinox Pharmaceuticals (Canada) Inc., +001 604 629 9223, clinical@aqxpharma.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 Nov 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Nov 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to evaluate the treatment effect of once daily administrations of AQX-1125 compared to placebo over 12 weeks on recurrent exacerbations as measured by EXACT (EXAcerbation of Chronic pulmonary disease Tool) in subjects with COPD following a recent exacerbation.
    Protection of trial subjects
    The study was conducted in accordance with the ethical principles of the “Declaration of Helsinki” and International Conference on Harmonization guideline on Good Clinical Practice (GCP). This clinical trial was reviewed and approved by the appropriate Regulatory Health Agency and Ethics Committee. Before entering the study, the informed consent form was read by and explained to all subjects. Participating subjects were required to sign the informed consent form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Nov 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    New Zealand: 6
    Country: Number of subjects enrolled
    United States: 104
    Country: Number of subjects enrolled
    Poland: 156
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    Denmark: 26
    Country: Number of subjects enrolled
    Finland: 8
    Country: Number of subjects enrolled
    Hungary: 83
    Country: Number of subjects enrolled
    Australia: 16
    Worldwide total number of subjects
    400
    EEA total number of subjects
    274
    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)
    186
    From 65 to 84 years
    211
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted in 8 countries: Australia, Denmark, Finland, Hungary, New Zealand, Poland, Sweden and US. US subjects participating in 6 month safety follow-up continued in the study until November 2015.

    Pre-assignment
    Screening details
    		 Four hundred subjects were randomized into two subsets: (1) Subjects suitable for outpatient treatment of a current exacerbation of COPD (within 3 days of diagnosis) & (2) Subjects who had been hospitalized in order to treat their exacerbation for not more than 7 days & were ready to be discharged or had been discharged within the last 3 days.

    Period 1
    Period 1 title
    Overall Trial (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
    		 AQX-1125
    Arm description
    		 AQX-1125 (200 mg capsule), oral once daily for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AQX-1125
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    AQX-1125 (200 mg capsule), oral once daily for 12 weeks.

    Arm title
    		 Placebo
    Arm description
    		 Placebo (matching AQX-1125 capsule), oral, once daily for 12 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo (matching AQX-1125 capsule), oral, once daily for 12 weeks.

    Number of subjects in period 1
    		AQX-1125 Placebo
    Started
    200
    200
    Completed
    169
    173
    Not completed
    31
    27
         Consent withdrawn by subject
    14
    13
         Physician decision
    4
    1
         Non-Compliance
    1
    -
         Adverse event, non-fatal
    6
    7
         Death
    1
    1
         COPD Exacerbation
    1
    1
         Sponsor Decision
    -
    1
         Lost to follow-up
    1
    1
         Protocol deviation
    3
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    AQX-1125
    Reporting group description
    		 AQX-1125 (200 mg capsule), oral once daily for 12 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo (matching AQX-1125 capsule), oral, once daily for 12 weeks.

    Reporting group values
    		 AQX-1125 Placebo Total
    Number of subjects
    		 200 200 400
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 86 100 186
        From 65-84 years
    		 113 98 211
        85 years and over
    		 1 2 3
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 65.8 ± 8.2 64.4 ± 8.5 -
    Gender categorical
    Units: Subjects
        Female
    		 99 91 190
        Male
    		 101 109 210
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 4 3 7
        Not Hispanic or Latino
    		 193 193 386
        Unknown or Not Reported
    		 3 4 7
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 11 9 20
        White
    		 188 189 377
        More than one race
    		 1 2 3
        Unknown or Not Reported
    		 0 0 0
    Region of Enrollment
    Units: Subjects
        New Zealand
    		 3 3 6
        Sweden
    		 0 1 1
        Hungary
    		 40 43 83
        United States
    		 51 53 104
        Finland
    		 5 3 8
        Denmark
    		 13 13 26
        Poland
    		 81 75 156
        Australia
    		 7 9 16
    Smoking Status
    Units: Subjects
        Current Smoker
    		 69 103 172
        Former Smoker
    		 131 97 228
    Nicotine Replacement Therapy Use
    Units: Subjects
        Yes
    		 196 195 391
        No
    		 4 5 9
    Body Mass Index
    Units: Kg/m2
        arithmetic mean (standard deviation)
    		 28.1 ± 6.6 27.2 ± 6.1 -
    Number of COPD Exacerbations in Last 18 months
    Units: Number of exacerbations/18 months
        arithmetic mean (standard deviation)
    		 3.1 ± 1.7 3.0 ± 1.4 -
    Number of Previous Hospitalizations for COPD
    Units: Number of previous hospitlizations
        arithmetic mean (standard deviation)
    		 1.1 ± 3.0 0.9 ± 1.6 -
    Years Since COPD Diagnosis
    Units: Years
        arithmetic mean (standard deviation)
    		 8.2 ± 5.7 7.8 ± 5.9 -
    Smoking Pack Years
    Units: pYears
        arithmetic mean (standard deviation)
    		 40.2 ± 22.0 41.2 ± 20.9 -
    Post-bronchodilator FEV1/FVC Ratio
    Units: Ratio
        arithmetic mean (standard deviation)
    		 0.51 ± 0.11 0.52 ± 0.11 -
    Post-bronchodilator FEV1% of Predicted
    Units: % Predicted
        arithmetic mean (standard deviation)
    		 50.2 ± 13.9 50.9 ± 13.2 -

    End points

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    End points reporting groups
    Reporting group title
    AQX-1125
    Reporting group description
    		 AQX-1125 (200 mg capsule), oral once daily for 12 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo (matching AQX-1125 capsule), oral, once daily for 12 weeks.

    Primary: Area Above Curve (AAC) on Daily Exact Score

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    End point title
    		 Area Above Curve (AAC) on Daily Exact Score
    End point description
    The primary variable (endpoint) of this study is the difference in the Area Above the Curve (AAC) for the daily EXACT score from baseline to Week 12 between subjects treated with AQX-1125 and placebo.The EXACT questionnaire is a patient reported outcome (PRO) measure designed to standardise the method for evaluating the frequency, severity and duration of acute exacerbations of COPD. The EXACT is a 14-item daily questionnaire where each item is assessed on a 5 or 6 point ordinal scale. Participants completed the EXACT questionnaire on a daily basis via an electronic diary from Day 1 (pre-dose) to Day 84 (week 12). Higher scores on the daily EXACT questionnaire indicate a more severe health state. When the post-treatment EXACT scores are lower (i.e. improved symptoms) than baseline EXACT, the AACs are positive.
    End point type
    Primary
    End point timeframe
    During the 12-week Treatment Period
    End point values
    		 AQX-1125 Placebo
    Number of subjects analysed
    179
    183
    Units: AAC on Daily Exact Score
        least squares mean (confidence interval 95%)
    415.4 (290.7 to 540.1)
    391.7 (268.2 to 515.1)
    Statistical analysis title
    		 AAC for Daily EXACT Scores During the 12-week TP
    Comparison groups
    AQX-1125 v Placebo
    Number of subjects included in analysis
    362
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.759
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    23.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -128.3
         upper limit
    		 175.7

    Secondary: Change From Baseline in COPD Assessment Tool (CAT) Score

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    End point title
    		 Change From Baseline in COPD Assessment Tool (CAT) Score
    End point description
    The secondary objective is to evaluate the treatment effect of once daily administrations of AQX-1125 compared to placebo over 12 weeks on the COPD Assessment Tool (CAT) score.The CAT questionnaire measures the impact of COPD on wellbeing and daily life. Participants answer 8 questions on a scale from 0 (best) to 5 (worst). The total score ranges from 0 to 40 with higher scores indicating more impact. A negative change from baseline indicates improvement. The change in total CAT score from Day 1, before taking study drug (baseline), to end of the 12 week treatment period was compared between the two treatments using an ANOVA model adjusting for treatment and region and including the baseline score as a covariate.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 AQX-1125 Placebo
    Number of subjects analysed
    179
    182
    Units: COPD Assessment Tool Score
        least squares mean (confidence interval 95%)
    -4.05 (-5.06 to -3.04)
    -3.71 (-4.71 to -2.71)
    Statistical analysis title
    		 Change From Baseline in COPD Assessment Tool (CAT)
    Comparison groups
    Placebo v AQX-1125
    Number of subjects included in analysis
    361
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.588
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.57
         upper limit
    		 0.89

    Secondary: Analysis of the Number of COPD Exacerbations (Medically Treated Event (MTE))

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    End point title
    		 Analysis of the Number of COPD Exacerbations (Medically Treated Event (MTE))
    End point description
    The secondary objective is to evaluate the treatment effect of once daily administrations of AQX-1125 compared to placebo over 12 weeks on the number of COPD exacerbations (MTE). COPD exacerbations were referred to as Medically Treated Exacerbations (MTEs) and identified as a change in symptoms and/or signs of COPD requiring prescription of one or both of: (1) Course of oral corticosteroids or (2) Antibiotic(s).
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 AQX-1125 Placebo
    Number of subjects analysed
    200
    198
    Units: Number of exacerbations/year
        least squares mean (confidence interval 95%)
    1.776 (1.374 to 2.297)
    1.641 (1.261 to 2.135)
    Statistical analysis title
    		 Number of COPD Exacerbations (MTE)
    Comparison groups
    AQX-1125 v Placebo
    Number of subjects included in analysis
    398
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.646
    Method
    		 Negative binomial regression model
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.771
         upper limit
    		 1.52

    Secondary: Time to First COPD Exacerbation

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    End point title
    		 Time to First COPD Exacerbation
    End point description
    Evaluate the treatment effect of once daily administrations of AQX-1125 compared to placebo over 12 weeks on the time to first exacerbation requiring medical intervention of oral corticosteroids and/or antibiotics.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 AQX-1125 Placebo
    Number of subjects analysed
    200
    198
    Units: Days
        arithmetic mean (standard deviation)
    38.1 ± 21.3
    43.9 ± 24.1
    No statistical analyses for this end point

    Secondary: Number of Subjects With at Least One COPD Exacerbation

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    End point title
    		 Number of Subjects With at Least One COPD Exacerbation
    End point description
    Number of subjects that presented with a COPD exacerbation during the 12 week treatment period.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 AQX-1125 Placebo
    Number of subjects analysed
    200
    198
    Units: Participants
    48
    51
    No statistical analyses for this end point

    Secondary: Change From Baseline in FEV1

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    End point title
    		 Change From Baseline in FEV1
    End point description
    Evaluate the treatment effect of once daily administrations of AQX-1125 compared to placebo over 12 weeks on forced expiratory volume in 1 second [FEV1]. FEV1 was determined from post-bronchodilator spirometry testing done at clinic visits.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 AQX-1125 Placebo
    Number of subjects analysed
    184
    185
    Units: litre(s)
        least squares mean (confidence interval 95%)
    -0.02 (-0.06 to 0.02)
    0.01 (-0.03 to 0.06)
    Statistical analysis title
    		 Change From Baseline in FEV1
    Comparison groups
    AQX-1125 v Placebo
    Number of subjects included in analysis
    369
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.226
    Method
    		 ANOVA
    Confidence interval

    Secondary: AQX-1125 Concentrations in Plasma (Trough Values)

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    End point title
    		 AQX-1125 Concentrations in Plasma (Trough Values)
    End point description
    Evaluate the pharmacokinetics (PK) of AQX-1125 in plasma.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    Number of subjects analysed
    Units: Micrograms per Liter
        geometric mean (geometric coefficient of variation)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    12 weeks treatment; up to 6 months safety follow-up.
    Adverse event reporting additional description
    SAEs listed occurred in >1 subjects per treatment arm.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    AQX-1125
    Reporting group description
    		 AQX-1125 (200 mg capsule), oral once daily for 12 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo (matching AQX-1125 capsule), oral, once daily for 12 weeks.

    Serious adverse events
    		 AQX-1125 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 200 (3.50%)
    12 / 200 (6.00%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    2 / 200 (1.00%)
    2 / 200 (1.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 200 (0.50%)
    8 / 200 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 200 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 AQX-1125 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 200 (10.50%)
    21 / 200 (10.50%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    12 / 200 (6.00%)
    13 / 200 (6.50%)
         occurrences all number
    12
    14
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    11 / 200 (5.50%)
    9 / 200 (4.50%)
         occurrences all number
    13
    9

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Jul 2013
    Clarification that the blood sample collection for biomarkers.
    18 Oct 2013
    Exclusion of women of child-bearing potential from being enrolled.
    07 Jan 2014
    Removal of biomarker sampling and analysis from the study. Clarification of the timing of the pulmonary function testing at each visit. Clarification of the time frame for the measurement of predicted FEV1 value in inclusion criterion No. 7.

    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.
    Secondary objective of "The frequency and severity of AEs and changes in physical exam, vital signs, ophthalmic exam, laboratory tests, weight, ECG, and con meds" was monitored throughout the study, clinically significant events were reported as AEs.
    For support, Contact us.
    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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