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    Clinical Trial Results:
    Randomized double-blind placebo-controlled prospective, parallel, multicentre clinical trial of bacterial polyvalent vaccine (BACTEK ®) administered by sublingual mucosa in subjects with chronic obstructive pulmonary disease (COPD) for efficacy evaluation, safety, and immunomodulatory response.

    Summary
    EudraCT number
    		 2012-003253-28
    Trial protocol
    		 ES  
    Global end of trial date
    23 Apr 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 May 2024
    First version publication date
    09 May 2024
    Other versions
    Summary report(s)
    		 MV130-SLG-001 Synopsis_23Apr24

    Trial information

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    Trial identification
    Sponsor protocol code
    MV130-SLG-001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01842360
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Inmunotek S.L.
    Sponsor organisation address
    calle Punto Mobi 5, Alcalá de Henares, Spain, 28805
    Public contact
    Miguel Casanovas; Medical Director, Inmunotek S.L., 34 912908942, mcasanovas@inmunotek.com
    Scientific contact
    Miguel Casanovas; Medical Director, Inmunotek S.L., 34 912908942, mcasanovas@inmunotek.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
    23 Apr 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Apr 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Apr 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of a bacterial vaccine administered sublingually, compared with placebo, in subjects with moderate and severe COPD based on the number of exacerbations of COPD .
    Protection of trial subjects
    All subjects received the first dose at the hospital and were trained in the proper administration of the drug. The subsequent doses were administered at subjects’s home. All adverse events that occurred during the course of the study were recorded and assessed. Protection of Personal Data and guarantee of digital rights. Regulation (Eu) 2016/679 of the European Parliament and of The Council of 27 April 2016 on the protection of natural persons with regard to the processing of personal data and on the free movement of such data, and repealing Directive 95/46/EC (General Data Protection Regulation). To ensure the rights of the subjects, the principal investigator or collaborating researchers, through the information sheet explained, the objectives and requirements of the study, the nature of the study drug, and its possible side effects, to the subject. The information to be provided includes: a description of the study endpoints, the methodology used, the type of treatment, the benefits that the subject may obtain from the treatment as well as the risks they may have and the right to withdraw from study if desired.
    Background therapy
    		 Currently, antibiotics remain the main strategy for the treatment of recurrent respiratory tract infections. However, these present with a number of limitations. In fact, we are currently in an antibiotic crisis due to the rapidly increasing antimicrobial resistance worldwide. In this sense, novel preventive strategies are urgently needed. A number of studies have demonstrated sublingual administration of Bactek (MV130) is able to significantly reduce the number of respiratory infectious clinical episodes in children and adults. The sublingual route for administration of bacterial preparations is very safe and effective for stimulating, in a strong and long-lasting way, the antigen-specific mucosa and the systemic humoral and cellular immunity. Stimulation of the oral mucosa may produce effects in the distant mucosa, by activating effector mechanisms of innate and acquired immunity through the mucosal associated lymphoid tissue (MALT). The oral cavity (inductive site) contains a high density of antigen-presenting cells with a high stimulating activity. These cells subsequently migrate to the lymph nodes, where they interact with T and B lymphocytes to induce their differentiation to effector cells. After their activation, the lymphocytes re-circulate through the different compartments of the mucosa-associated lymphoid tissue (MALT), and access different mucous membranes, including the respiratory tract (effector site).
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Apr 2013
    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
    Spain: 198
    Worldwide total number of subjects
    198
    EEA total number of subjects
    198
    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)
    61
    From 65 to 84 years
    137
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The time of recruitment was between May 2013 (first patient enrolled) and July 2019 (last patient enrolled).

    Pre-assignment
    Screening details
    		 This study included adult subjects diagnosed of moderate or severe COPD (3 or more moderate or severe exaerbations in the previous year). Subjects screened were 198. Number of subjects who received treatment (excluded screening failures) were 142. Efficacy evaluable population (Intention-to-treat) were 198. The immunological study were 60.

    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, Monitor, Data analyst
    Blinding implementation details
    Neither the investigator nor the subject knew about the treatment provided. The members of the investigator team, the monitoring team and the people responsible for analysing the data did not have access to blinded data either. The Researcher/Pharmacist had a way to break the code due to an emergency. The code break would only have been carried out in emergencies, in the case the researcher needed to know in order to provide appropriate medical treatment or to ensure the safety of the subjects.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group I Active treatment for 12 months + 6 months follow-up
    Arm description
    		 Sublingual MV130 treatment at a dose of 300 FTU. Subjects in Group I received active treatment consisting of a whole-cell inactivated bacterial vaccine sublingually for 12 months (i.e. MV130 12M).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bactek
    Investigational medicinal product code
    MV130
    Other name
    Pharmaceutical forms
    Sublingual spray
    Routes of administration
    Sublingual use
    Dosage and administration details
    Sublingual MV130 treatment at a dose of 300 FTU, administered to 97 subjects with recurrent moderate or severe COPD exacerbations, daily for 12 months. The active trial medication was a polyvalent bacterial vaccine; the pharmaceutical form was a glycerinated suspension containing a mixture of four inactivated non-lysate bacterial concentrates (V101 Staphylococcus epidermidis 15%, V102 Staphylococcus aureus 15%, V104 Streptococcus pneumoniae 60%, V113 Klebsiella pneumoniae 4%, V103 Haemophilus influenzae 3%, Moraxella catarrhalis 3%) as active substance, at a final concentration of 300 Formazin Turbidity Units (FTU). As excipients, it contains 0.63 g of glycerol, artificial pineapple flavouring (0.01 mL), sodium chloride (9 mg) and water (q.s. for 1 mL) per mL. The trial medication was administered through the sublingual route, applying two sprays daily.

    Arm title
    		 Group II placebo for 12 months + 6 months follow-up
    Arm description
    		 Subjects in Group II received placebo sublingually for 12 months.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Placebo
    Other name
    Pharmaceutical forms
    Sublingual spray
    Routes of administration
    Sublingual use
    Dosage and administration details
    It contained an identical solution to the test product but no active substance (without the inactivated non-lysate bacterial concentrates), and was administrated through the sublingual route, applying two sprays daily. The composition was glycerol 0.63 g, artificial pineapple flavouring 0.01 mL, sodium chloride 9 mg and water (q.s. for 1 mL) per mL.

    Number of subjects in period 1
    		Group I Active treatment for 12 months + 6 months follow-up Group II placebo for 12 months + 6 months follow-up
    Started
    97
    101
    Completed
    63
    79
    Not completed
    34
    22
         Consent withdrawn by subject
    24
    9
         Adverse event, non-fatal
    3
    5
         Non compliance
    2
    1
         Discontinued intervention
    2
    1
         Lost to follow-up
    3
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group I Active treatment for 12 months + 6 months follow-up
    Reporting group description
    		 Sublingual MV130 treatment at a dose of 300 FTU. Subjects in Group I received active treatment consisting of a whole-cell inactivated bacterial vaccine sublingually for 12 months (i.e. MV130 12M).

    Reporting group title
    Group II placebo for 12 months + 6 months follow-up
    Reporting group description
    		 Subjects in Group II received placebo sublingually for 12 months.

    Reporting group values
    		 Group I Active treatment for 12 months + 6 months follow-up Group II placebo for 12 months + 6 months follow-up Total
    Number of subjects
    		 97 101 198
    Age categorical
    Individuals aged 44–84 years were enrolled. The median age was 72.0 [interquartile range, IQR, 65.0–77.0] and 68 [IQR, 61.0–76.0] years for groups receiving placebo and MV130 respectively.
    Units: Subjects
        Adults (18-64 years)
    		 30 31 61
        From 65-84 years
    		 67 70 137
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 68.0 (61.0 to 76.0) 72.0 (65.0 to 77.0) -
    Gender categorical
    Adult subjects with a definite diagnosis of moderate or severe COPD (3 or more moderate or severe COPD exacerbations in the previous 12 months).
    Units: Subjects
        Female
    		 19 25 44
        Male
    		 78 76 154
    Subject analysis sets

    Subject analysis set title
    Efficacy ITT evaluable population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    As stated in the protocol, efficacy analyses were carried out by intention-to-treat (ITT). Evaluable ITT population included all randomized subjects. The background and demographic data was described in the ITT population according to the treatment assignment at randomization.

    Subject analysis set title
    Efficacy PP evaluable population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Evaluable per-protocol population included randomized subjects who completed the efficacy period and adequately complied with the protocol.

    Subject analysis set title
    Immunological study
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The planned number of subjects included in the trial but also in the immunological sub-study was 60.

    Subject analysis set title
    Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety analysis included all randomized subjects, i.e. 198 individuals: 101 placebo (P) and 97 MV130.

    Subject analysis sets values
    		 Efficacy ITT evaluable population Efficacy PP evaluable population Immunological study Safety
    Number of subjects
    198
    142
    60
    198
    Age categorical
    Individuals aged 44–84 years were enrolled. The median age was 72.0 [interquartile range, IQR, 65.0–77.0] and 68 [IQR, 61.0–76.0] years for groups receiving placebo and MV130 respectively.
    Units: Subjects
        Adults (18-64 years)
    61
    63
    61
        From 65-84 years
    137
    79
    137
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    69.0 (63 to 76)
    68.8 (63 to 75)
    69.0 (63 to 76)
    Gender categorical
    Adult subjects with a definite diagnosis of moderate or severe COPD (3 or more moderate or severe COPD exacerbations in the previous 12 months).
    Units: Subjects
        Female
    44
    35
    44
        Male
    154
    107
    154

    End points

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    End points reporting groups
    Reporting group title
    Group I Active treatment for 12 months + 6 months follow-up
    Reporting group description
    		 Sublingual MV130 treatment at a dose of 300 FTU. Subjects in Group I received active treatment consisting of a whole-cell inactivated bacterial vaccine sublingually for 12 months (i.e. MV130 12M).

    Reporting group title
    Group II placebo for 12 months + 6 months follow-up
    Reporting group description
    		 Subjects in Group II received placebo sublingually for 12 months.

    Subject analysis set title
    Efficacy ITT evaluable population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    As stated in the protocol, efficacy analyses were carried out by intention-to-treat (ITT). Evaluable ITT population included all randomized subjects. The background and demographic data was described in the ITT population according to the treatment assignment at randomization.

    Subject analysis set title
    Efficacy PP evaluable population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Evaluable per-protocol population included randomized subjects who completed the efficacy period and adequately complied with the protocol.

    Subject analysis set title
    Immunological study
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The planned number of subjects included in the trial but also in the immunological sub-study was 60.

    Subject analysis set title
    Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety analysis included all randomized subjects, i.e. 198 individuals: 101 placebo (P) and 97 MV130.

    Primary: Number of COPD exacerbations due to infectious episodes.

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    End point title
    		 Number of COPD exacerbations due to infectious episodes.
    End point description
    End point type
    Primary
    End point timeframe
    Comparison in the number of COPD episodes in the two study groups in the 18-month study period.
    End point values
    		 Group I Active treatment for 12 months + 6 months follow-up Group II placebo for 12 months + 6 months follow-up Efficacy ITT evaluable population Efficacy PP evaluable population
    Number of subjects analysed
    97
    101
    198
    142
    Units: episodes
        median (inter-quartile range (Q1-Q3))
    2.0 (1.0 to 3.0)
    3.0 (1.0 to 5.0)
    2.0 (1.0 to 4.0)
    2.0 (1.0 to 4.8)
    Statistical analysis title
    		 Median number of COPD exacerbations.
    Comparison groups
    Group I Active treatment for 12 months + 6 months follow-up v Group II placebo for 12 months + 6 months follow-up
    Number of subjects included in analysis
    198
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.01
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation

    Secondary: Decrease in the rate of COPD exacerbations per study group at 12 months (end of the trial treatment) and 6 months after the trial’s termination (follow-up).

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    End point title
    		 Decrease in the rate of COPD exacerbations per study group at 12 months (end of the trial treatment) and 6 months after the trial’s termination (follow-up).
    End point description
    Incidence is the number of new events per total subjects in the sample population. Incidence frequency is the number of events in a period, usually one year.
    End point type
    Secondary
    End point timeframe
    The 18 months duration of the study by person-years incidence rates and incidence-risk ratio.
    End point values
    		 Group I Active treatment for 12 months + 6 months follow-up Group II placebo for 12 months + 6 months follow-up Efficacy ITT evaluable population
    Number of subjects analysed
    97
    101
    198
    Units: rate
        number (not applicable)
    1.86
    2.67
    2.30
    Statistical analysis title
    		 Incidence-rate comparison
    Statistical analysis description
    Incidence is the number of new events per total subjects in the sample. Incidence frequency is the number of events in a period, usually one year. Thus, we see that the incidence of exacerbations in one year per treatment group of MV130/Placebo treatment group is 1.87/2.68 (≈1.9/2.7) new exacerbations which is a difference of 0.81 (0.44-1.18) exacerbations between the two groups and a P<0.001. This is called incidence rate.
    Comparison groups
    Group I Active treatment for 12 months + 6 months follow-up v Group II placebo for 12 months + 6 months follow-up v Efficacy ITT evaluable population
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Poisson
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Secondary: Decrease in severity of COPD exacerbations.

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    End point title
    		 Decrease in severity of COPD exacerbations.
    End point description
    The severity of exacerbations was to be measured by the consumption of health care resources: ED/Hospitalisation/ICU/Consultations visits, as follows: ICU hospitalisation 4 points Hospitalisation 3 points Emergency room visit 2 points Consultation resulting in change in usual treatment 1 point
    End point type
    Secondary
    End point timeframe
    18 months.
    End point values
    		 Group I Active treatment for 12 months + 6 months follow-up Group II placebo for 12 months + 6 months follow-up Efficacy ITT evaluable population
    Number of subjects analysed
    97
    101
    198
    Units: points
        median (inter-quartile range (Q1-Q3))
    1 (0 to 5)
    3 (1 to 23)
    2 (0 to 9)
    Statistical analysis title
    		 Decrease in COPD exacerbation severity
    Statistical analysis description
    The mean of health care consumption was 17.5±34.7 points in the placebo group versus 9.2±27.9 points in the MV130 group.
    Comparison groups
    Group II placebo for 12 months + 6 months follow-up v Group I Active treatment for 12 months + 6 months follow-up v Efficacy ITT evaluable population
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0094
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation

    Secondary: Time elapsed between the start of the treatment and the first COPD exacerbation.

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    End point title
    		 Time elapsed between the start of the treatment and the first COPD exacerbation.
    End point description
    For reference, median survival or event-free times are reported with the 95% CI of the median.
    End point type
    Secondary
    End point timeframe
    18 months.
    End point values
    		 Group I Active treatment for 12 months + 6 months follow-up Group II placebo for 12 months + 6 months follow-up Efficacy ITT evaluable population
    Number of subjects analysed
    97
    101
    198
    Units: time
        median (confidence interval 95%)
    6.35 (4.41 to 9.00)
    4.42 (3.38 to 6.61)
    5.52 (4.06 to 6.61)
    Statistical analysis title
    		 Time free of events
    Statistical analysis description
    The median time to first event in the placebo group is 4.4 months and in the treatment group is 6.4 months.
    Comparison groups
    Group I Active treatment for 12 months + 6 months follow-up v Group II placebo for 12 months + 6 months follow-up v Efficacy ITT evaluable population
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3917
    Method
    		 Logrank
    Parameter type
    		 Median difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard error of the mean

    Secondary: Use of drugs (antibiotics, corticosteroids, etc).

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    End point title
    		 Use of drugs (antibiotics, corticosteroids, etc).
    End point description
    The use of drugs will be calculated using the following index: - antibiotics: 1 point - inhaled corticosteroids: 2 points - sistemic corticosteroids: 3 points - use of oxyygen: 4 points - use of mechanical ventilation: 5 points
    End point type
    Secondary
    End point timeframe
    18 months.
    End point values
    		 Group I Active treatment for 12 months + 6 months follow-up Group II placebo for 12 months + 6 months follow-up Efficacy ITT evaluable population
    Number of subjects analysed
    97
    101
    198
    Units: points
        median (inter-quartile range (Q1-Q3))
    24 (0 to 71)
    40 (9 to 112)
    30 (3 to 84)
    Statistical analysis title
    		 Total use of drugs
    Statistical analysis description
    The use of oxygen and mechanical ventilation is not available. The other three index are used. As for the previous index the number of days with any of these drugs is used.
    Comparison groups
    Group I Active treatment for 12 months + 6 months follow-up v Group II placebo for 12 months + 6 months follow-up v Efficacy ITT evaluable population
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0232
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation

    Secondary: Number of hospitalizations due to COPD exacerbations.

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    End point title
    		 Number of hospitalizations due to COPD exacerbations.
    End point description
    There were 26 hospitalizations in 16 patients in the MV130 group versus 51 hospitalizations in 29 patients in the placebo group (Fisher's exact test of the number of patients, P=0.044). The same patient could have more than one hospitalizations.
    End point type
    Secondary
    End point timeframe
    18 months.
    End point values
    		 Group I Active treatment for 12 months + 6 months follow-up Group II placebo for 12 months + 6 months follow-up Efficacy ITT evaluable population
    Number of subjects analysed
    97
    101
    198
    Units: number
        median (inter-quartile range (Q1-Q3))
    0.0 (0.0 to 0.0)
    0.0 (0.0 to 1.0)
    0.0 (0.0 to 0.0)
    Statistical analysis title
    		 Number of hospitalizations per patient.
    Statistical analysis description
    The mean number of hospitalizations in the MV130 group was 0.27±0.91 and in the placebo group 0.5±1.05 hospitalizations (exact MW, P=0.042).In relation to ICU stay, there were only 3 ICU stays: 1 in the MV130 group (6 days duration) and 2 in the placebo group (6 and 13 days duration).
    Comparison groups
    Group II placebo for 12 months + 6 months follow-up v Group I Active treatment for 12 months + 6 months follow-up v Efficacy ITT evaluable population
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0319
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation

    Secondary: Days of hospitalization due to COPD exacerbations.

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    End point title
    		 Days of hospitalization due to COPD exacerbations.
    End point description
    End point type
    Secondary
    End point timeframe
    18 months.
    End point values
    		 Group I Active treatment for 12 months + 6 months follow-up Group II placebo for 12 months + 6 months follow-up Efficacy ITT evaluable population
    Number of subjects analysed
    97
    101
    198
    Units: days
        median (inter-quartile range (Q1-Q3))
    0 (0 to 0)
    0 (0 to 6)
    0 (0 to 0)
    Statistical analysis title
    		 Hospitalisation days
    Statistical analysis description
    The mean number of days of hospitalization in the MV130 group is 2.1 and in the placebo group 4.1 days. Significant differences (P=0.0264) can be observed.
    Comparison groups
    Group I Active treatment for 12 months + 6 months follow-up v Group II placebo for 12 months + 6 months follow-up v Efficacy ITT evaluable population
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0264
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Secondary: Number of visits to the Emergency Room.

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    End point title
    		 Number of visits to the Emergency Room.
    End point description
    End point type
    Secondary
    End point timeframe
    18 months.
    End point values
    		 Group I Active treatment for 12 months + 6 months follow-up Group II placebo for 12 months + 6 months follow-up Efficacy ITT evaluable population
    Number of subjects analysed
    97
    101
    198
    Units: number
        median (inter-quartile range (Q1-Q3))
    0 (0 to 0)
    0 (0 to 1)
    0 (0 to 1)
    Statistical analysis title
    		 Mean number of emergency room visits
    Statistical analysis description
    The mean number of emergency room visits was 0.37 (±1.15) for the MV130 group and 0.87 (±1.61) for the placebo group.
    Comparison groups
    Group II placebo for 12 months + 6 months follow-up v Group I Active treatment for 12 months + 6 months follow-up v Efficacy ITT evaluable population
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0037
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation

    Secondary: Number of unscheduled medical consultations due to COPD exacerbations.

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    End point title
    		 Number of unscheduled medical consultations due to COPD exacerbations.
    End point description
    End point type
    Secondary
    End point timeframe
    18 months.
    End point values
    		 Group I Active treatment for 12 months + 6 months follow-up Group II placebo for 12 months + 6 months follow-up Efficacy ITT evaluable population
    Number of subjects analysed
    97
    101
    198
    Units: number
        median (inter-quartile range (Q1-Q3))
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    Statistical analysis title
    		 median number of unshcedueled medical visits
    Statistical analysis description
    The mean number of emergency room visits was 0.08 (±0.31) for the MV130 group and 0.31 (±0.88) for the placebo group.
    Comparison groups
    Group I Active treatment for 12 months + 6 months follow-up v Group II placebo for 12 months + 6 months follow-up v Efficacy ITT evaluable population
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1008
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation

    Secondary: Health-related quality of life, as determined by an adapted version of the specific CAT test.

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    End point title
    		 Health-related quality of life, as determined by an adapted version of the specific CAT test.
    End point description
    End point type
    Secondary
    End point timeframe
    18 months.
    End point values
    		 Group I Active treatment for 12 months + 6 months follow-up Group II placebo for 12 months + 6 months follow-up Efficacy ITT evaluable population
    Number of subjects analysed
    97
    101
    198
    Units: Points
        median (inter-quartile range (Q1-Q3))
    -1.5 (-7.0 to 1.5)
    -1.0 (-5.0 to 3.0)
    -1.0 (-6.0 to 2.0)
    Statistical analysis title
    		 Mean differences in CAT score
    Statistical analysis description
    Statistical analysis of differences at 12 months is shown as it is the treatment time period. The difference between study groups is 2.2 (CI 95% -4.3, -0.14). At 18 months the difference is of 1.5 points (CI 95% -3.8, 0.7).
    Comparison groups
    Group I Active treatment for 12 months + 6 months follow-up v Group II placebo for 12 months + 6 months follow-up v Efficacy ITT evaluable population
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0367
    Method
    		 t-test, 2-sided
    Parameter type
    		 Median difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation

    Secondary: Healthcare expenditure resulting from resource consumption during episodes of COPD exacerbations occurring during the trial period.

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    End point title
    		 Healthcare expenditure resulting from resource consumption during episodes of COPD exacerbations occurring during the trial period.
    End point description
    Healthcare expenditure was assessed as the sum of: - Complementary tests - Programmed visits to the specialist - Total number of visits to the specialist - Non-programmed visits to the specialist - ICU hospitalization days - Vists to the emergency room - Days hospitalized - Sum of antibiotics - Number of visits to GP - Sum of oral corticosteroids - Number of telephone calls to the GP - Sum of inhalers - Home visits - Sum of antipyretics The total consumption of medical resources was addedd for the placebo and MV130 groups. Differences in total score were evaluated and related to healthcare expenditure. A sum of the total resource consumption showed a total score of 8231 in the placebo group compared with 5202 in the MV130 group, showing a 36.8% resource consumption reduction and thus a direct association with a reduction in healthcare expenditure.
    End point type
    Secondary
    End point timeframe
    18 months.
    End point values
    		 Group I Active treatment for 12 months + 6 months follow-up Group II placebo for 12 months + 6 months follow-up
    Number of subjects analysed
    97
    101
    Units: sum
    5202
    8231
    No statistical analyses for this end point

    Secondary: Adverse events and overall tolerability (adverse reactions).

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    End point title
    		 Adverse events and overall tolerability (adverse reactions).
    End point description
    Total number of adverse events in Active (MV130) and Placebo groups were compared.
    End point type
    Secondary
    End point timeframe
    18 months.
    End point values
    		 Group I Active treatment for 12 months + 6 months follow-up Group II placebo for 12 months + 6 months follow-up Safety
    Number of subjects analysed
    97
    101
    198
    Units: Number
    116
    113
    229
    Statistical analysis title
    		 Differences in total number of adverse events.
    Statistical analysis description
    The total number of adverse events were 229, from them 113 (49.6%) were from the placebo group and 116 (50.4%) were from the active group. These 229 events were experienced in 103 subjects, 49 (48.5%) from the placebo group, while 54 (55.6%) belonging to group receiving MV130. No significant differences between treatment groups were found (Fisher's exact test, P=0.3234).
    Comparison groups
    Group I Active treatment for 12 months + 6 months follow-up v Group II placebo for 12 months + 6 months follow-up v Safety
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3234
    Method
    		 Fisher exact
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    18 months.
    Adverse event reporting additional description
    Safety was evaluated throughout the study by recording all adverse events and all adverse reactions.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Group I active treatment for 12 months + 6 months follow-up
    Reporting group description
    		 -

    Reporting group title
    Group II placebo for 12 months + 6 months follow-up
    Reporting group description
    		 -

    Serious adverse events
    		 Group I active treatment for 12 months + 6 months follow-up Group II placebo for 12 months + 6 months follow-up
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 97 (8.25%)
    12 / 101 (11.88%)
         number of deaths (all causes)
    1
    2
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to central nervous system
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain neoplasm
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma pancreas
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Unstable angina
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Surgery
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Petit mal epilepsy
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 97 (0.00%)
    2 / 101 (1.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Apendicitis
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         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
    Pulmonary embolism
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 97 (1.03%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary aspergillosis
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Mycobacterium avium complex infection
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 101 (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: 1%
    Non-serious adverse events
    		 Group I active treatment for 12 months + 6 months follow-up Group II placebo for 12 months + 6 months follow-up
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    45 / 97 (46.39%)
    36 / 101 (35.64%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Prostatic adenoma
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Thyroid adenoma
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Phlebitis
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Intermittent claudication
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Surgical and medical procedures
    Cholecystectomy
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Circumcision
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Dental implantation
         subjects affected / exposed
    1 / 97 (1.03%)
    1 / 101 (0.99%)
         occurrences all number
    1
    1
    Hernia repair
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Pterygium operation
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Surgery
    Additional description: Surgery due to inversion of left eye lid.
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Tooth extraction
         subjects affected / exposed
    1 / 97 (1.03%)
    3 / 101 (2.97%)
         occurrences all number
    1
    4
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 97 (0.00%)
    3 / 101 (2.97%)
         occurrences all number
    0
    3
    Oedema peripheral
         subjects affected / exposed
    1 / 97 (1.03%)
    1 / 101 (0.99%)
         occurrences all number
    1
    1
    Temperature regulation disorder
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Pyrexia
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Seasonal allergy
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    2 / 97 (2.06%)
    2 / 101 (1.98%)
         occurrences all number
    2
    2
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 97 (1.03%)
    1 / 101 (0.99%)
         occurrences all number
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Acute sinusitis
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Catarrh
         subjects affected / exposed
    1 / 97 (1.03%)
    1 / 101 (0.99%)
         occurrences all number
    1
    1
    Dysphonia
         subjects affected / exposed
    1 / 97 (1.03%)
    1 / 101 (0.99%)
         occurrences all number
    1
    1
    Epistaxis
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Laryngeal oedema
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    2 / 97 (2.06%)
    0 / 101 (0.00%)
         occurrences all number
    2
    0
    Pharyngitis
         subjects affected / exposed
    3 / 97 (3.09%)
    0 / 101 (0.00%)
         occurrences all number
    5
    0
    Pharyngotonsillitis
         subjects affected / exposed
    2 / 97 (2.06%)
    1 / 101 (0.99%)
         occurrences all number
    2
    1
    Rhinitis
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Sinusitis
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Tonsillitis
         subjects affected / exposed
    2 / 97 (2.06%)
    1 / 101 (0.99%)
         occurrences all number
    2
    1
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 97 (5.15%)
    8 / 101 (7.92%)
         occurrences all number
    5
    9
    Investigations
    Lumbar puncture
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Postoperative wound infection
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Epicondylitis
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Foot fracture
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Fall
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    anemia postoperative
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Upper limb fracture
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Animal bite
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    2 / 97 (2.06%)
    0 / 101 (0.00%)
         occurrences all number
    3
    0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 97 (0.00%)
    2 / 101 (1.98%)
         occurrences all number
    0
    3
    Atrial fibrillation
         subjects affected / exposed
    1 / 97 (1.03%)
    3 / 101 (2.97%)
         occurrences all number
    1
    3
    Tachycardia
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Syncope
         subjects affected / exposed
    1 / 97 (1.03%)
    1 / 101 (0.99%)
         occurrences all number
    1
    1
    Sciatica
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Paraesthesia
         subjects affected / exposed
    1 / 97 (1.03%)
    1 / 101 (0.99%)
         occurrences all number
    1
    1
    Dizziness
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 97 (1.03%)
    1 / 101 (0.99%)
         occurrences all number
    1
    1
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Eye disorders
    Blepharitis
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Conjunctival haemorrhage
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Eye disorder
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Uveitis
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    1 / 97 (1.03%)
    2 / 101 (1.98%)
         occurrences all number
    1
    2
    Colitis
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Constipation
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 101 (0.00%)
         occurrences all number
    2
    0
    Diarrhoea
         subjects affected / exposed
    4 / 97 (4.12%)
    1 / 101 (0.99%)
         occurrences all number
    4
    1
    Gastroenteritis
         subjects affected / exposed
    1 / 97 (1.03%)
    1 / 101 (0.99%)
         occurrences all number
    1
    1
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    2
    Haemorrhoids
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Inguinal hernia
         subjects affected / exposed
    1 / 97 (1.03%)
    1 / 101 (0.99%)
         occurrences all number
    1
    1
    Large intestine polyp
         subjects affected / exposed
    2 / 97 (2.06%)
    0 / 101 (0.00%)
         occurrences all number
    2
    0
    Odynophagia
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Rectal haemorrhage
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Tooth disorder
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Purpura senile
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Dermatitis
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Urticaria
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Pruritus
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Renal colic
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Urinary incontinence
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Urinary retention
         subjects affected / exposed
    2 / 97 (2.06%)
    1 / 101 (0.99%)
         occurrences all number
    2
    1
    Urinary tract infection
         subjects affected / exposed
    8 / 97 (8.25%)
    3 / 101 (2.97%)
         occurrences all number
    13
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 97 (6.19%)
    1 / 101 (0.99%)
         occurrences all number
    7
    1
    Back pain
         subjects affected / exposed
    7 / 97 (7.22%)
    1 / 101 (0.99%)
         occurrences all number
    7
    2
    Gout
         subjects affected / exposed
    0 / 97 (0.00%)
    2 / 101 (1.98%)
         occurrences all number
    0
    2
    Gouty arthritis
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    invertebral disc protusion
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Muscle contracture
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Myalgia
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Myopathy
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Pain in extremity
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Synovial cyst
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Tendonitis
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Infections and infestations
    Abcess
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Ear lobe infection
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Gingivitis
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    helocibacter infection
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Herpes zoster
         subjects affected / exposed
    1 / 97 (1.03%)
    1 / 101 (0.99%)
         occurrences all number
    1
    1
    Oral candidiasis
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Oral herpes
         subjects affected / exposed
    0 / 97 (0.00%)
    2 / 101 (1.98%)
         occurrences all number
    0
    2
    Otitis media acute
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Parotitis
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Periodontitis
         subjects affected / exposed
    3 / 97 (3.09%)
    1 / 101 (0.99%)
         occurrences all number
    4
    1
    Postoperative wound infection
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Skin infection
         subjects affected / exposed
    1 / 97 (1.03%)
    1 / 101 (0.99%)
         occurrences all number
    1
    1
    Tooth abscess
         subjects affected / exposed
    1 / 97 (1.03%)
    2 / 101 (1.98%)
         occurrences all number
    1
    2
    Tooth infection
         subjects affected / exposed
    1 / 97 (1.03%)
    3 / 101 (2.97%)
         occurrences all number
    1
    3
    Viral infection
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Diabetes mellitus
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Sep 2012
    - Added details on IMP, administration schedule, study population, permitted medication. - Added clarification on identical formula for all patients. - Study objective and variables homogenized. - Parameters from pharmacogenetic study included. - Justification for 30% reduction in the number of exacerbations included compared to placebo. - Minor typographical corrections.
    21 Jun 2013
    -Two new investigators were included, and one was removed. -Added details on administration instructions. - Added subjects suffering severe COPD. - Clarification about when the visits were performed. - Changes on exclusion/inclusion criteria.
    12 Feb 2014
    A new study site was included: Hospital Universitario Torrejón de Ardoz.
    10 Mar 2014
    A new study site was included: Hospital 12 de Octubre.
    29 Oct 2014
    An inclusion criterion was modified (induced sputum instead of bronchoalveolar lavage).
    26 Oct 2015
    A new study site was included: Hospital Universitario La Paz.
    21 Jun 2016
    Minor typographical corrections.
    09 Jan 2017
    A new study site was included: Hospital Universitario de Vic.
    21 Jun 2017
    Minor typographical corrections.
    29 Dec 2017
    Minor typographical corrections.

    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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