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    Clinical Trial Results:
    A Phase 2, Randomized, Double-blind, Placebo-controlled, Efficacy and Safety Study of Inhaled JNJ-49095397 (RV568) in Subjects With Moderate to Severe Chronic Obstructive Pulmonary Disease

    Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
    Summary
    EudraCT number
    		 2012-005184-27
    Trial protocol
    		 BE   GB   DE   HU   CZ   NL   PL   RO  
    Global end of trial date
    01 Sep 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Apr 2016
    First version publication date
    22 Apr 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    49095397OPD2001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01867762
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Janssen-Cilag International NV
    Sponsor organisation address
    Archimedesweg 29-2333CM, Leiden, Netherlands, 2333CM
    Public contact
    Clinical Registry Group, Janssen-Cilag International NV, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen-Cilag International NV, ClinicalTrialsEU@its.jnj.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
    01 Sep 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Sep 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study was to assess the efficacy (as measured by change from baseline in prebronchodilator [preBD] percent predicted forced expiratory volume in 1 second [FEV1]) of JNJ-49095397 compared with placebo in subjects with symptomatic moderate (global initiative for chronic obstructive lung disease [GOLD] Grade II) to severe (GOLD Grade III) chronic obstructive pulmonary disease (COPD).
    Protection of trial subjects
    The safety assessments included the incidence and severity of adverse events (AEs), clinical laboratory tests (hematology, serum chemistry and urinalysis), electrocardiogram (ECG), vital signs and physical examinations which were assessed throughout the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Aug 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    Canada: 26
    Country: Number of subjects enrolled
    Czech Republic: 18
    Country: Number of subjects enrolled
    Germany: 35
    Country: Number of subjects enrolled
    United Kingdom: 13
    Country: Number of subjects enrolled
    Hungary: 17
    Country: Number of subjects enrolled
    Netherlands: 11
    Country: Number of subjects enrolled
    Poland: 25
    Country: Number of subjects enrolled
    Romania: 9
    Country: Number of subjects enrolled
    Russian Federation: 25
    Country: Number of subjects enrolled
    United States: 26
    Worldwide total number of subjects
    211
    EEA total number of subjects
    134
    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)
    108
    From 65 to 84 years
    103
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 211 subjects were randomized in the study out of these 106 subjects were randomized to the placebo group and 105 subjects were randomized to the JNJ-49095397 400 microgram (µg) group.

    Period 1
    Period 1 title
    Overall Study Period (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
    		 Subjects received Placebo capsule oral inhalation once daily using dry powder inhaler for 12 Weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Subjects received Placebo once daily by using a dry powder inhaler for 12 weeks.

    Arm title
    		 JNJ-49095397
    Arm description
    		 Subjects received JNJ-49095397 400 µg capsule oral inhalation once daily using dry powder inhaler for 12 Weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    JNJ-49095397
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Subjects received JNJ-49095397 400 µg once daily by using a dry powder inhaler for 12 weeks.

    Number of subjects in period 1
    		Placebo JNJ-49095397
    Started
    106
    105
    Completed
    85
    92
    Not completed
    21
    13
         Consent withdrawn by subject
    3
    2
         Adverse event, non-fatal
    11
    6
         Other
    6
    4
         Adverse event, serious non-fatal
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received Placebo capsule oral inhalation once daily using dry powder inhaler for 12 Weeks.

    Reporting group title
    JNJ-49095397
    Reporting group description
    		 Subjects received JNJ-49095397 400 µg capsule oral inhalation once daily using dry powder inhaler for 12 Weeks.

    Reporting group values
    		 Placebo JNJ-49095397 Total
    Number of subjects
    		 106 105 211
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 52 56 108
        From 65 to 84 years
    		 54 49 103
        85 years and over
    		 0 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.5 ± 7.08 63.7 ± 7.69 -
    Title for Gender
    Units: subjects
        Female
    		 41 42 83
        Male
    		 65 63 128

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received Placebo capsule oral inhalation once daily using dry powder inhaler for 12 Weeks.

    Reporting group title
    JNJ-49095397
    Reporting group description
    		 Subjects received JNJ-49095397 400 µg capsule oral inhalation once daily using dry powder inhaler for 12 Weeks.

    Primary: Change From Baseline in preBD (before taking an inhaled bronchodilator) Percent-predicted Forced Expiratory Volume in one Second (FEV1) at Week 12

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    End point title
    		 Change From Baseline in preBD (before taking an inhaled bronchodilator) Percent-predicted Forced Expiratory Volume in one Second (FEV1) at Week 12
    End point description
    FEV1 is the amount of air that can be forcibly exhaled in one second after a maximal inhalation. FEV1 will be measured by spirometry. A positive change from baseline in FEV1 indicates improvement in lung function. The data are shown in two ways in the 'end point values' table below. The first display is 'per cent predicted' where the absolute value of FEV1 (in Liters) is compared to a normal population of the same age, height and gender. The second value displayed is change from baseline at week 12 in per cent predicted which is the primary endpoint. The modified intent-to-treat (mITT) analysis set included all randomized subjects who received at least one dose of study agent and had at least 1 post treatment efficacy measurement. Here, ‘n’ signifies number of subjects analyzed for this endpoint at given timepoint.
    End point type
    Primary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo JNJ-49095397
    Number of subjects analysed
    106
    105
    Units: percent change
    arithmetic mean (standard deviation)
        Baseline (n= 106, 105)
    49.33 ± 9.649
    48.8 ± 9.525
        Change in percent predicted at Week 12(n= 106,104)
    -1.94 ± 5.748
    -1.75 ± 6.037
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Placebo v JNJ-49095397
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.838
    Method
    		 ANCOVA
    Parameter type
    		 Least square (LS) mean difference
    Point estimate
    0.17
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -1.18
         upper limit
    		 1.51
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.815

    Secondary: Change From Baseline in Postbronchodilator (postBD, after taking an inhaled bronchodilator) Percent-Predicted FEV1 at Week 12

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    End point title
    		 Change From Baseline in Postbronchodilator (postBD, after taking an inhaled bronchodilator) Percent-Predicted FEV1 at Week 12
    End point description
    FEV1 is the amount of air that can be forcibly exhaled in one second after a maximal inhalation. FEV1 will be measured by spirometry. A positive change from baseline in FEV1 indicates improvement in lung function. The data are shown in two ways in the 'end point values' table below. The first display is 'per cent predicted' where the absolute value of FEV1 (in Liters) is compared to a normal population of the same age, height and gender. The second value displayed is change from baseline at week 12 in per cent predicted which is the primary endpoint. The mITT analysis set included all randomized subjects who received at least one dose of study agent and had at least 1 post treatment efficacy measurement. Here, ‘n’ signifies number of subjects analyzed for this endpoint at given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo JNJ-49095397
    Number of subjects analysed
    106
    105
    Units: percent change
    arithmetic mean (standard deviation)
        Baseline (n= 106, 105)
    53.91 ± 9.05
    53.59 ± 8.929
        Change in percent predicted at Week 12(n= 104,104)
    -1.87 ± 5.79
    -1.78 ± 4.996
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Placebo v JNJ-49095397
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.894
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    0.1
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -1.14
         upper limit
    		 1.35
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.754

    Secondary: Change From Baseline in Weekly Average Number of Occasions in a day That Rescue Medication is Used at Week 12

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    End point title
    		 Change From Baseline in Weekly Average Number of Occasions in a day That Rescue Medication is Used at Week 12
    End point description
    Use of inhaled rescue medication (expressed as the number of occasions) taken on a schedule and/or for control of symptoms will be recorded twice daily. The mITT analysis set included all randomized subjects who received at least one dose of study agent and had at least 1 post treatment efficacy measurement. Here, ‘n’ signifies number of subjects analyzed for this endpoint at given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo JNJ-49095397
    Number of subjects analysed
    106
    105
    Units: number
    arithmetic mean (standard deviation)
        Baseline (n= 106, 105)
    2.57 ± 1.985
    2.43 ± 2.373
        Change at Week 12 (n= 105, 104)
    0.07 ± 1.552
    -0.08 ± 1.641
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Placebo v JNJ-49095397
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.407
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -0.18
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.53
         upper limit
    		 0.18
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.213

    Secondary: Change From Baseline in Exacerbations of Chronic Pulmonary Disease Tool-Respiratory Symptoms (E-RS) Total Score at Week 12

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    End point title
    		 Change From Baseline in Exacerbations of Chronic Pulmonary Disease Tool-Respiratory Symptoms (E-RS) Total Score at Week 12
    End point description
    E-RS is an 11-items respiratory system scoring algorithm to assess the severity of respiratory symptoms in participants with COPD. Each item has either 5 or 6 response options. Higher score indicates more severe COPD. The mITT analysis set included all randomized subjects who received at least 1 dose of study agent and had at least 1 post treatment efficacy measurement. Here, ‘n’ signifies number of subjects analyzed for this endpoint at given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo JNJ-49095397
    Number of subjects analysed
    106
    105
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n= 106, 105)
    13.09 ± 6.35
    11.97 ± 6.1
        Change at Week 12 (n= 105, 104)
    -0.01 ± 4.446
    -0.38 ± 3.57
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Placebo v JNJ-49095397
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.363
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -0.51
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -1.43
         upper limit
    		 0.41
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.557

    Secondary: Change From Baseline in the Total Score of the St. George's Respiratory Questionnaire for COPD Subjects (SGRQ-C) at Week 12

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    End point title
    		 Change From Baseline in the Total Score of the St. George's Respiratory Questionnaire for COPD Subjects (SGRQ-C) at Week 12
    End point description
    SGRQ-C is a 40-item questionnaire designed to measure health impairment in participants with COPD. SGRQ-C is divided into two components: 1) symptoms, 2) activity & impacts. Total SGRQ-C score ranges from 0 (best) and 100 (worst). Higher scores indicate greater health impairment. The mITT analysis set included all randomized subjects who received at least 1 dose of study agent and had at least one post treatment efficacy measurement. Here, ‘n’ signifies number of subjects analyzed for this endpoint at given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline to week 12
    End point values
    		 Placebo JNJ-49095397
    Number of subjects analysed
    106
    105
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n= 106, 105)
    49.67 ± 15.584
    47.96 ± 18.889
        Change at Week 12 (n= 104, 104)
    -1.88 ± 11.454
    0.88 ± 11.25
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Placebo v JNJ-49095397
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.111
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    2.47
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.08
         upper limit
    		 5.02
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.544

    Secondary: Number of Subjects With Adverse Events

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    End point title
    		 Number of Subjects With Adverse Events
    End point description
    An adverse event is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product.
    End point type
    Secondary
    End point timeframe
    Up to Week 16
    End point values
    		 Placebo JNJ-49095397
    Number of subjects analysed
    106
    105
    Units: subjects
    57
    54
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to follow up (up to Week 16)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    JNJ-49095397 400µg
    Reporting group description
    		 Daily inhalation of JNJ-49095397 400 µg for 12 weeks

    Reporting group title
    PLACEBO
    Reporting group description
    		 Daily inhalation of Placebo for 12 weeks

    Serious adverse events
    		 JNJ-49095397 400µg PLACEBO
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 105 (2.86%)
    5 / 106 (4.72%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    Cardiac disorders
    Myocardial Infarction
         subjects affected / exposed
    0 / 105 (0.00%)
    2 / 106 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial Ischaemia
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    1 / 105 (0.95%)
    2 / 106 (1.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Spondylolisthesis
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pyelonephritis
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 JNJ-49095397 400µg PLACEBO
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 105 (20.95%)
    22 / 106 (20.75%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 105 (0.95%)
    6 / 106 (5.66%)
         occurrences all number
    1
    7
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    13 / 105 (12.38%)
    14 / 106 (13.21%)
         occurrences all number
    15
    21
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    9 / 105 (8.57%)
    6 / 106 (5.66%)
         occurrences all number
    10
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 May 2013
    The amendment includes the following substantial changes: The reference was removed to RVH008 (internal study designation) as alternate name of study to avoid confusion. Text was clarified indicating that the assessments at Study Visit 7 should be performed in the event of early withdrawal from the study. The safety follow-up electrocardiogram (ECG) was moved from Study Visit 8 to Study Visit 7. It updated and clarified text on nonclinical safety pharmacology, and nonclinical genotoxicity, updated text to reflect completed clinical studies and data, and update the dose rationale. Clarified text on summary of safety from clinical studies, removed unnecessary assessment for inventory of study agent at Study Visit 8. Clarification of text on inclusion criterion and reporting for subjects with laboratory values outside normal reference ranges during screening and clarification of inclusion criterion text on use of contraception. The text was clarified on changes to background medications and for storage conditions.
    10 Oct 2013
    In a subset of consenting subjects in selected countries and sites, additional PK blood samples were added to the study procedures at the week 8 study visit. Prior scheduled PK assessments were adjusted in this subset. The text was clarified on exclusion criteria regarding previous episodes of COPD exacerbations.

    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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    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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