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    Clinical Trial Results:
    Randomized, double-blind, placebo-controlled, multicenter study comparing Ciprofloxacin DPI 32.5 mg BID intermittently administered for 28 days on / 28 days off or 14 days on / 14 days off versus placebo to evaluate the time to first pulmonary exacerbation and frequency of exacerbations in subjects with non–cystic fibrosis bronchiectasis.

    Summary
    EudraCT number
    		 2013-004659-19
    Trial protocol
    		 DE   NL   LT   AT   CZ   PT   BG   LV   SK  
    Global end of trial date
    19 Oct 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Aug 2017
    First version publication date
    19 Aug 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BAYQ3939/15626
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02106832
    WHO universal trial number (UTN)
    		 U1111-1150-8425
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, Leverkusen, Germany, D-51368
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.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
    19 Oct 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Oct 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of this study were • To evaluate the efficacy of ciprofloxacin DPI administered 2 times a day (BID) intermittently for 28 days on study treatment / 28 days off study treatment or 14 days on study treatment / 14 days off study treatment to prolong the time to first pulmonary exacerbation requiring an intervention with systemic antibiotics (oral/i.v.) in subjects with non–CF BE within 48 weeks after start of treatment (as agreed with the US FDA [Food and Drug Administration]). • To evaluate the efficacy of ciprofloxacin DPI administered 2 times a day (BID) intermittently for 28 days on study treatment / 28 days off study treatment or 14 days on study treatment / 14 days off study treatment in reducing the frequency of pulmonary exacerbation requiring an intervention with systemic antibiotics (oral/i.v.) in subjects with non–CF BE within 48 weeks after start of treatment.
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent form was read by and explained to all subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    		 Subjects were allowed to stay on their non-antibiotic standard treatment.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Apr 2014
    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
    Poland: 39
    Country: Number of subjects enrolled
    Portugal: 14
    Country: Number of subjects enrolled
    Romania: 32
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Netherlands: 19
    Country: Number of subjects enrolled
    Bulgaria: 54
    Country: Number of subjects enrolled
    Czech Republic: 4
    Country: Number of subjects enrolled
    Germany: 19
    Country: Number of subjects enrolled
    Latvia: 45
    Country: Number of subjects enrolled
    Lithuania: 6
    Country: Number of subjects enrolled
    Argentina: 13
    Country: Number of subjects enrolled
    Australia: 21
    Country: Number of subjects enrolled
    Brazil: 5
    Country: Number of subjects enrolled
    China: 33
    Country: Number of subjects enrolled
    Hong Kong: 9
    Country: Number of subjects enrolled
    Korea, Republic of: 34
    Country: Number of subjects enrolled
    Philippines: 10
    Country: Number of subjects enrolled
    Russian Federation: 60
    Country: Number of subjects enrolled
    Serbia: 33
    Country: Number of subjects enrolled
    South Africa: 2
    Country: Number of subjects enrolled
    Taiwan: 9
    Country: Number of subjects enrolled
    Thailand: 13
    Country: Number of subjects enrolled
    Turkey: 30
    Country: Number of subjects enrolled
    United States: 16
    Worldwide total number of subjects
    521
    EEA total number of subjects
    233
    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)
    299
    From 65 to 84 years
    218
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study was conducted at 164 study centers in 25 countries between 30 April 2014 (first subject first visit) and 19 October 2016 (last subject last visit).

    Pre-assignment
    Screening details
    		 A total of 1123 subjects were screened and 521 subjects were randomized. The randomized subjects were allocated to treatment groups, and 2 subjects in the Cipro 14 group did not receive study medication.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ciprofloxacin DPI 28 Days on/off (Cipro 28)
    Arm description
    		 Subjects received ciprofloxacin (BAYQ3939) 32.5 milligram (mg) corresponding to 50 mg dry powder for inhalation (DPI) administered twice daily (BID) (every 12 hours); a treatment cycle consisted of a 28-day on-treatment phase followed by a 28-day off-treatment phase (48 weeks treatment phase = 6 active cycles).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ciprofloxacin DPI
    Investigational medicinal product code
    BAYQ3939
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Ciprofloxacin dry powder for inhalation (DPI) 32.5 mg inhaled twice daily in cycles of 28 days on-treatment and 28 days off-treatment.

    Arm title
    		 Ciprofloxacin DPI 14 Days on/off (Cipro 14)
    Arm description
    		 Subjects received ciprofloxacin 32.5 mg corresponding to 50 mg DPI administered BID (every 12 hours); a treatment cycle consisted of a 14-day on-treatment phase followed by a 14-day off-treatment phase (48 weeks treatment phase = 12 active cycles).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ciprofloxacin DPI
    Investigational medicinal product code
    BAYQ3939
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Ciprofloxacin DPI 32.5 mg inhaled twice daily in cycles of 14 days on-treatment and 14 days off-treatment.

    Arm title
    		 Placebo 28 Days on/off (Placebo 28)
    Arm description
    		 Subjects received placebo matched to ciprofloxacin 32.5 mg powder (containing 40 mg dry powder) administered BID (every 12 hours); a treatment cycle consisted of a 28-day on-treatment phase followed by a 28-day off-treatment phase (48 weeks treatment phase = 6 cycles).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Matching placebo inhaled twice daily intermittently for 28 days on / 28 days off.

    Arm title
    		 Placebo 14 Days on/off (Placebo 14)
    Arm description
    		 Subjects received placebo matched to ciprofloxacin 32.5 mg powder (containing 40 mg dry powder) administered BID (every 12 hours); a treatment cycle consisted of a 14-day on-treatment phase followed by a 14-day off-treatment phase (48 weeks treatment phase = 12 cycles).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Matching placebo inhaled twice daily intermittently for 14 days on / 14 days off.

    Number of subjects in period 1
    		Ciprofloxacin DPI 28 Days on/off (Cipro 28) Ciprofloxacin DPI 14 Days on/off (Cipro 14) Placebo 28 Days on/off (Placebo 28) Placebo 14 Days on/off (Placebo 14)
    Started
    171
    176
    86
    88
    Treated
    171
    174
    86
    88
    Completed
    148
    151
    70
    73
    Not completed
    23
    25
    16
    15
         Consent withdrawn by subject
    17
    17
    10
    7
         Physician decision
    1
    -
    -
    -
         Deterioration of general conditions
    -
    -
    1
    -
         Adverse event, non-fatal
    1
    2
    3
    -
         Technical problems
    -
    1
    -
    -
         Death
    4
    4
    1
    4
         Lost to follow-up
    -
    1
    1
    3
         Protocol deviation
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ciprofloxacin DPI 28 Days on/off (Cipro 28)
    Reporting group description
    		 Subjects received ciprofloxacin (BAYQ3939) 32.5 milligram (mg) corresponding to 50 mg dry powder for inhalation (DPI) administered twice daily (BID) (every 12 hours); a treatment cycle consisted of a 28-day on-treatment phase followed by a 28-day off-treatment phase (48 weeks treatment phase = 6 active cycles).

    Reporting group title
    Ciprofloxacin DPI 14 Days on/off (Cipro 14)
    Reporting group description
    		 Subjects received ciprofloxacin 32.5 mg corresponding to 50 mg DPI administered BID (every 12 hours); a treatment cycle consisted of a 14-day on-treatment phase followed by a 14-day off-treatment phase (48 weeks treatment phase = 12 active cycles).

    Reporting group title
    Placebo 28 Days on/off (Placebo 28)
    Reporting group description
    		 Subjects received placebo matched to ciprofloxacin 32.5 mg powder (containing 40 mg dry powder) administered BID (every 12 hours); a treatment cycle consisted of a 28-day on-treatment phase followed by a 28-day off-treatment phase (48 weeks treatment phase = 6 cycles).

    Reporting group title
    Placebo 14 Days on/off (Placebo 14)
    Reporting group description
    		 Subjects received placebo matched to ciprofloxacin 32.5 mg powder (containing 40 mg dry powder) administered BID (every 12 hours); a treatment cycle consisted of a 14-day on-treatment phase followed by a 14-day off-treatment phase (48 weeks treatment phase = 12 cycles).

    Reporting group values
    		 Ciprofloxacin DPI 28 Days on/off (Cipro 28) Ciprofloxacin DPI 14 Days on/off (Cipro 14) Placebo 28 Days on/off (Placebo 28) Placebo 14 Days on/off (Placebo 14) Total
    Number of subjects
    		 171 176 86 88 521
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.3 ± 14.2 60.4 ± 13.7 60.6 ± 13.7 60.4 ± 15 -
    Gender categorical
    Units: Subjects
        Female
    		 92 96 52 62 302
        Male
    		 79 80 34 26 219
    Saint George's Respiratory Questionnaire (SGRQ) Symptoms Component Score (n=169, 170, 85, 83)
    The SGRQ was a validated, disease-specific instrument that measures health-related quality of life (HRQoL) in adults with chronic obstructive pulmonary disease (COPD) and asthma and was later validated for use in bronchiectasis. The SGRQ covers 3 dimensions: symptoms, activity and impact on daily life. To determine the outcome, a score ranging from 1 to 100 was calculated for each individual domain and for the total score, and smaller scores indicate better health status. For this outcome measure, the symptoms component score was reported.
    Units: Score on a scale
        arithmetic mean (standard deviation)
    		 60.75 ± 20.61 61.26 ± 19.54 58.56 ± 19.17 63.47 ± 19.48 -
    QoL-B Respiratory Symptoms Domain Score (n= 104, 115, 56, 59)
    The Quality of Life Questionnaire for Bronchiectasis (QoL-B) was a disease-specific questionnaire developed for non-Cystic fibrosis Bronchiectasis. It covers 8 dimensions: physical functioning, role functioning, emotional functioning, social functioning, vitality, treatment burden, health perceptions, and respiratory symptoms. Each dimension was scored separately on a scale of 0 to 100, and higher scores represent better outcomes. For this outcome measure, the respiratory symptoms domain score was reported.
    Units: Score on a scale
        arithmetic mean (standard deviation)
    		 50.14 ± 19.07 52.17 ± 18.49 53.95 ± 16 48.67 ± 17.72 -
    Forced Expiratory Volume in One Second (FEV1)
    FEV1 was the maximal volume of air exhaled in the first second of a forced expiration from a position of full inspiration, expressed in liters at body temperature and ambient pressure saturated with water vapor (BTPS).
    Units: Liter
        arithmetic mean (standard deviation)
    		 1.569 ± 0.602 1.519 ± 0.617 1.56 ± 0.692 1.477 ± 0.558 -

    End points

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    End points reporting groups
    Reporting group title
    Ciprofloxacin DPI 28 Days on/off (Cipro 28)
    Reporting group description
    		 Subjects received ciprofloxacin (BAYQ3939) 32.5 milligram (mg) corresponding to 50 mg dry powder for inhalation (DPI) administered twice daily (BID) (every 12 hours); a treatment cycle consisted of a 28-day on-treatment phase followed by a 28-day off-treatment phase (48 weeks treatment phase = 6 active cycles).

    Reporting group title
    Ciprofloxacin DPI 14 Days on/off (Cipro 14)
    Reporting group description
    		 Subjects received ciprofloxacin 32.5 mg corresponding to 50 mg DPI administered BID (every 12 hours); a treatment cycle consisted of a 14-day on-treatment phase followed by a 14-day off-treatment phase (48 weeks treatment phase = 12 active cycles).

    Reporting group title
    Placebo 28 Days on/off (Placebo 28)
    Reporting group description
    		 Subjects received placebo matched to ciprofloxacin 32.5 mg powder (containing 40 mg dry powder) administered BID (every 12 hours); a treatment cycle consisted of a 28-day on-treatment phase followed by a 28-day off-treatment phase (48 weeks treatment phase = 6 cycles).

    Reporting group title
    Placebo 14 Days on/off (Placebo 14)
    Reporting group description
    		 Subjects received placebo matched to ciprofloxacin 32.5 mg powder (containing 40 mg dry powder) administered BID (every 12 hours); a treatment cycle consisted of a 14-day on-treatment phase followed by a 14-day off-treatment phase (48 weeks treatment phase = 12 cycles).

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    included subjects who were randomized.

    Subject analysis set title
    Safety analysis set (SAF)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    included subjects who were randomized and received study medication.

    Subject analysis set title
    Pooled Placebo
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received matching placebo matched to ciprofloxacin 32.5 mg powder (containing 40 mg dry powder) administered BID (every 12 hours); a treatment cycle consisted of either a 28-day days on-treatment phase followed by 28-day off-treatment phase or 14-day on-treatment phase followed by 14-day off treatment phase (48 weeks treatment phase = 6 cycles and 12 cycles, respectively).

    Primary: Number of participants with exacerbation events with worsening of at least three signs/symptoms over 48 weeks

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    End point title
    		 Number of participants with exacerbation events with worsening of at least three signs/symptoms over 48 weeks
    End point description
    For this outcome measure, exacerbation events were defined as exacerbations with systemic antibiotic use and presence of fever or malaise / fatigue and worsening of at least three signs/symptoms over 48 weeks.
    End point type
    Primary
    End point timeframe
    Up to Week 48
    End point values
    		 Ciprofloxacin DPI 28 Days on/off (Cipro 28) Ciprofloxacin DPI 14 Days on/off (Cipro 14) Placebo 28 Days on/off (Placebo 28) Placebo 14 Days on/off (Placebo 14)
    Number of subjects analysed
    171 [1]
    176 [2]
    86 [3]
    88 [4]
    Units: Subjects with exacerbation events
    number (not applicable)
        Number of exacerbations: 0
    115
    108
    51
    50
        Number of exacerbations: 1
    46
    40
    18
    23
        Number of exacerbations: 2
    8
    23
    10
    9
        Number of exacerbations: 3
    2
    4
    5
    5
        Number of exacerbations: 4
    0
    1
    1
    1
        Number of exacerbations: 5
    0
    0
    1
    0
    Notes
    [1] - FAS
    [2] - FAS
    [3] - FAS
    [4] - FAS
    Statistical analysis title
    		 Cipro 28 vs Placebo 28
    Statistical analysis description
    A Poisson regression with adjustment for over-/under dispersion was used to analyze the number of exacerbation events over 48 weeks and to test the difference in the frequency of exacerbation between Ciprofloxacin DPI 28 and the matching placebo 28. P-value was analysed using Wald-type test along with the incidence rate ratio of the comparison.
    Comparison groups
    Ciprofloxacin DPI 28 Days on/off (Cipro 28) v Placebo 28 Days on/off (Placebo 28)
    Number of subjects included in analysis
    257
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0014
    Method
    		 Poisson regression
    Parameter type
    		 Incidence Rate Ratio
    Point estimate
    0.5493
    Confidence interval
         level
    		 99.9%
         sides
    2-sided
         lower limit
    		 0.2968
         upper limit
    		 1.0164
    Statistical analysis title
    		 Cipro 14 vs Placebo 14
    Statistical analysis description
    A Poisson regression with adjustment for over-/under dispersion was used to analyze the number of exacerbation events over 48 weeks and to test the difference in the frequency of exacerbation between Ciprofloxacin DPI 14 and the matching placebo 14. P-value was analysed using Wald-type test along with the incidence rate ratio of the comparison.
    Comparison groups
    Ciprofloxacin DPI 14 Days on/off (Cipro 14) v Placebo 14 Days on/off (Placebo 14)
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2862
    Method
    		 Poisson regression
    Parameter type
    		 Incidence Rate Ratio
    Point estimate
    0.8313
    Confidence interval
         level
    		 95.1%
         sides
    2-sided
         lower limit
    		 0.5911
         upper limit
    		 1.1691

    Secondary: Time to First Exacerbation Event Within 48 Weeks - Cipro 28 vs. Pooled Placebo

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    End point title
    		 Time to First Exacerbation Event Within 48 Weeks - Cipro 28 vs. Pooled Placebo [5]
    End point description
    Time to first exacerbation was defined as the time from randomization until the visit at which the first qualifying exacerbation is recorded by the investigator. Exacerbation events are defined as exacerbations with systemic antibiotic use and presence of fever or malaise / fatigue and worsening of at least three signs/symptoms. An entry of ‘99999’ indicates that the value could not be estimated due to too many censored observations.
    End point type
    Secondary
    End point timeframe
    Up to Week 48
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pooled placebo group data were reported in place of individual placebo groups.
    End point values
    		 Ciprofloxacin DPI 28 Days on/off (Cipro 28) Pooled Placebo
    Number of subjects analysed
    171 [6]
    174 [7]
    Units: Days
        median (confidence interval 99.9%)
    99999 (99999 to 99999)
    99999 (211 to 99999)
    Notes
    [6] - FAS
    [7] - FAS
    No statistical analyses for this end point

    Secondary: Time to First Exacerbation Event Within 48 Weeks - Cipro 14 vs. Pooled Placebo

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    End point title
    		 Time to First Exacerbation Event Within 48 Weeks - Cipro 14 vs. Pooled Placebo [8]
    End point description
    Time to first exacerbation was defined as the time from randomization until the visit at which the first qualifying exacerbation is recorded by the investigator. Exacerbation events are defined as exacerbations with systemic antibiotic use and presence of fever or malaise / fatigue and worsening of at least three signs/symptoms. An entry of ‘99999’ indicates that the value could not be estimated due to too many censored observations.
    End point type
    Secondary
    End point timeframe
    Up to Week 48
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pooled placebo group data were reported in place of individual placebo groups.
    End point values
    		 Ciprofloxacin DPI 14 Days on/off (Cipro 14) Pooled Placebo
    Number of subjects analysed
    176 [9]
    174 [10]
    Units: Days
        median (confidence interval 95.1%)
    99999 (99999 to 99999)
    99999 (278 to 99999)
    Notes
    [9] - FAS
    [10] - FAS
    No statistical analyses for this end point

    Secondary: Number of participants with exacerbation events with worsening of at least one sign/symptom over 48 weeks

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    End point title
    		 Number of participants with exacerbation events with worsening of at least one sign/symptom over 48 weeks
    End point description
    For this outcome measure, exacerbation events were defined as exacerbations with systemic antibiotic use and worsening of at least one sign/symptom over 48 weeks.
    End point type
    Secondary
    End point timeframe
    Up to Week 48
    End point values
    		 Ciprofloxacin DPI 28 Days on/off (Cipro 28) Ciprofloxacin DPI 14 Days on/off (Cipro 14) Placebo 28 Days on/off (Placebo 28) Placebo 14 Days on/off (Placebo 14)
    Number of subjects analysed
    171 [11]
    176 [12]
    86 [13]
    88 [14]
    Units: Subjects with exacerbation events
    number (not applicable)
        Number of exacerbations: 0
    102
    96
    44
    46
        Number of exacerbations: 1
    51
    46
    21
    24
        Number of exacerbations: 2
    14
    26
    13
    9
        Number of exacerbations: 3
    3
    4
    5
    6
        Number of exacerbations: 4
    1
    3
    2
    2
        Number of exacerbations: 5
    0
    1
    1
    1
    Notes
    [11] - FAS
    [12] - FAS
    [13] - FAS
    [14] - FAS
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Pathogen Eradication at End of Treatment (Week 44/46)

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    End point title
    		 Percentage of Subjects With Pathogen Eradication at End of Treatment (Week 44/46) [15]
    End point description
    Pathogen eradication was defined as a negative culture result for all pre-specified pathogens at end of treatment (week 44 or 46 depending on treatment regimen) that were present in the participant at baseline. There was no imputation for participants who discontinued the study prematurely.
    End point type
    Secondary
    End point timeframe
    End of treatment (Week 44/46)
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pooled placebo group data were reported in place of individual placebo groups.
    End point values
    		 Ciprofloxacin DPI 28 Days on/off (Cipro 28) Ciprofloxacin DPI 14 Days on/off (Cipro 14) Pooled Placebo
    Number of subjects analysed
    171 [16]
    176 [17]
    174 [18]
    Units: Percentage of subjects
    number (not applicable)
        No
    35.1
    35.8
    40.2
        Yes
    31.6
    35.8
    31.6
    Notes
    [16] - Full analysis set (FAS) included participants who were randomized.
    [17] - Full analysis set (FAS) included participants who were randomized.
    [18] - Full analysis set (FAS) included participants who were randomized.
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in Patient Reported Outcome Saint George's Respiratory Questionnaire (SGRQ) Symptoms Component Score at End of Treatment (Week 44/46)

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    End point title
    		 Mean Change From Baseline in Patient Reported Outcome Saint George's Respiratory Questionnaire (SGRQ) Symptoms Component Score at End of Treatment (Week 44/46)
    End point description
    The SGRQ was a validated, disease-specific instrument that measures health-related quality of life (HRQoL) in adults with chronic obstructive pulmonary disease (COPD) and asthma and was later validated for use in bronchiectasis. The SGRQ covers 3 dimensions: symptoms, activity and impact on daily life. To determine the outcome, a score ranging from 1 to 100 was calculated for each individual domain and for the total score, and smaller scores indicate better health status. For this outcome measure, the symptoms component score was reported.
    End point type
    Secondary
    End point timeframe
    Baseline and end of treatment (Week 44/46)
    End point values
    		 Ciprofloxacin DPI 28 Days on/off (Cipro 28) Ciprofloxacin DPI 14 Days on/off (Cipro 14) Placebo 28 Days on/off (Placebo 28) Placebo 14 Days on/off (Placebo 14)
    Number of subjects analysed
    142 [19]
    142 [20]
    67 [21]
    72 [22]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -8.92 ± 21.06
    -9.02 ± 20.1
    -2.91 ± 24.48
    -11.5 ± 18.54
    Notes
    [19] - FAS with participants evaluable for this outcome measure.
    [20] - FAS with participants evaluable for this outcome measure.
    [21] - FAS with participants evaluable for this outcome measure.
    [22] - FAS with participants evaluable for this outcome measure.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Occurrence of New Pathogens Present at End of Treatment (Week 44/46)

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    End point title
    		 Percentage of Subjects With Occurrence of New Pathogens Present at End of Treatment (Week 44/46) [23]
    End point description
    New pathogens were any of the pre-specified organisms not cultured before start of study medication. There was no imputation for participants who discontinued the study prematurely.
    End point type
    Secondary
    End point timeframe
    End of treatment (Week 44/46)
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pooled placebo group data were reported in place of individual placebo groups.
    End point values
    		 Ciprofloxacin DPI 28 Days on/off (Cipro 28) Ciprofloxacin DPI 14 Days on/off (Cipro 14) Pooled Placebo
    Number of subjects analysed
    171 [24]
    176 [25]
    174 [26]
    Units: Percentage of subjects
    number (not applicable)
        No
    62.6
    67.6
    61.5
        Yes
    4.1
    4
    10.3
    Notes
    [24] - Full analysis set (FAS) included participants who were randomized.
    [25] - Full analysis set (FAS) included participants who were randomized.
    [26] - Full analysis set (FAS) included participants who were randomized.
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in Patient Reported Outcome Quality of Life Questionnaire for Bronchiectasis (QoL-B) Respiratory Symptoms Domain Score at End of Treatment (Week 44/46)

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    End point title
    		 Mean Change From Baseline in Patient Reported Outcome Quality of Life Questionnaire for Bronchiectasis (QoL-B) Respiratory Symptoms Domain Score at End of Treatment (Week 44/46)
    End point description
    The QoL-B was a disease-specific questionnaire developed for non-Cystic fibrosis Bronchiectasis. It covers 8 dimensions: physical functioning, role functioning, emotional functioning, social functioning, vitality, treatment burden, health perceptions, and respiratory symptoms. Each dimension was scored separately on a scale of 0 to 100, and higher scores represent better outcomes. For this outcome measure, the respiratory symptoms domain score was reported.
    End point type
    Secondary
    End point timeframe
    Baseline and end of treatment (Week 44/46)
    End point values
    		 Ciprofloxacin DPI 28 Days on/off (Cipro 28) Ciprofloxacin DPI 14 Days on/off (Cipro 14) Placebo 28 Days on/off (Placebo 28) Placebo 14 Days on/off (Placebo 14)
    Number of subjects analysed
    85 [27]
    94 [28]
    43 [29]
    49 [30]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    11.57 ± 17.49
    10.9 ± 18.07
    7.08 ± 17
    10.7 ± 15.58
    Notes
    [27] - FAS with participants evaluable for this outcome measure.
    [28] - FAS with participants evaluable for this outcome measure.
    [29] - FAS with participants evaluable for this outcome measure.
    [30] - FAS with participants evaluable for this outcome measure.
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at End of Treatment (Week 44/46)

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    End point title
    		 Mean Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at End of Treatment (Week 44/46)
    End point description
    FEV1 was defined as the maximal volume of air exhaled in the first second of a forced expiration from a position of full inspiration, expressed in liters at body temperature and ambient pressure saturated with water vapor (BTPS).
    End point type
    Secondary
    End point timeframe
    Baseline and end of treatment (Week 44/46)
    End point values
    		 Ciprofloxacin DPI 28 Days on/off (Cipro 28) Ciprofloxacin DPI 14 Days on/off (Cipro 14) Placebo 28 Days on/off (Placebo 28) Placebo 14 Days on/off (Placebo 14)
    Number of subjects analysed
    138 [31]
    140 [32]
    62 [33]
    71 [34]
    Units: Liter
        arithmetic mean (standard deviation)
    0.038 ± 0.336
    -0.037 ± 0.287
    -0.038 ± 0.272
    0.037 ± 0.299
    Notes
    [31] - FAS with participants evaluable for this outcome measure.
    [32] - FAS with participants evaluable for this outcome measure.
    [33] - FAS with participants evaluable for this outcome measure.
    [34] - FAS with participants evaluable for this outcome measure.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study treatment up to 30 days after the last study drug administration
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Ciprofloxacin DPI 28 Days on/off (Cipro 28)
    Reporting group description
    		 Subjects received ciprofloxacin (BAYQ3939) 32.5 mg corresponding to 50 mg DPI administered BID (every 12 hours); a treatment cycle consisted of a 28-day on-treatment phase followed by a 28-day off-treatment phase (48 weeks treatment phase = 6 active cycles).

    Reporting group title
    Ciprofloxacin DPI 14 Days on/off (Cipro 14)
    Reporting group description
    		 Subjects received ciprofloxacin 32.5 mg corresponding to 50 mg DPI administered BID (every 12 hours); a treatment cycle consisted of a 14-day on-treatment phase followed by a 14-day off-treatment phase (48 weeks treatment phase = 12 active cycles).

    Reporting group title
    Pooled Placebo
    Reporting group description
    		 Subjects received matching placebo matched to ciprofloxacin 32.5 mg powder (containing 40 mg dry powder) administered BID (every 12 hours); a treatment cycle consisted of either a 28-day days on-treatment phase followed by 28-day off-treatment phase or 14-day on-treatment phase followed by 14-day off treatment phase (48 weeks treatment phase = 6 cycles and 12 cycles, respectively).

    Serious adverse events
    		 Ciprofloxacin DPI 28 Days on/off (Cipro 28) Ciprofloxacin DPI 14 Days on/off (Cipro 14) Pooled Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    28 / 171 (16.37%)
    45 / 174 (25.86%)
    41 / 174 (23.56%)
         number of deaths (all causes)
    4
    5
    5
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 174 (0.57%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 171 (0.00%)
    0 / 174 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Glottis carcinoma
         subjects affected / exposed
    0 / 171 (0.00%)
    0 / 174 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemangioma
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 174 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal carcinoma
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 174 (0.57%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 171 (0.00%)
    0 / 174 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    0 / 171 (0.00%)
    0 / 174 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 174 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Adenomyosis
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 174 (0.57%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchiectasis
         subjects affected / exposed
    17 / 171 (9.94%)
    24 / 174 (13.79%)
    21 / 174 (12.07%)
         occurrences causally related to treatment / all
    0 / 20
    0 / 27
    0 / 31
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    0 / 2
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 171 (0.00%)
    3 / 174 (1.72%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 171 (0.00%)
    0 / 174 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    2 / 171 (1.17%)
    3 / 174 (1.72%)
    4 / 174 (2.30%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 174 (0.57%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 174 (0.57%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 174 (0.57%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 171 (0.00%)
    0 / 174 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 174 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cor pulmonale
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 174 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Congestive cardiomyopathy
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 174 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 174 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 174 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carotid artery occlusion
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 174 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 174 (0.57%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 171 (0.00%)
    0 / 174 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Meniere's disease
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 174 (0.57%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Vitreous detachment
         subjects affected / exposed
    0 / 171 (0.00%)
    0 / 174 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 174 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulum intestinal
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 174 (0.57%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 174 (0.57%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 174 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal obstruction
         subjects affected / exposed
    0 / 171 (0.00%)
    0 / 174 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 171 (0.00%)
    0 / 174 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric disorder
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 174 (0.57%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    0 / 171 (0.00%)
    0 / 174 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 174 (0.57%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 171 (0.00%)
    0 / 174 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 174 (0.57%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 174 (0.57%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Chronic sinusitis
         subjects affected / exposed
    0 / 171 (0.00%)
    0 / 174 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 171 (0.00%)
    0 / 174 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 171 (0.00%)
    0 / 174 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 171 (1.75%)
    2 / 174 (1.15%)
    2 / 174 (1.15%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 171 (0.00%)
    0 / 174 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 171 (0.00%)
    0 / 174 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 174 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis bacterial
         subjects affected / exposed
    0 / 171 (0.00%)
    0 / 174 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 174 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infective exacerbation of bronchiectasis
         subjects affected / exposed
    0 / 171 (0.00%)
    3 / 174 (1.72%)
    2 / 174 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoproteinaemia
         subjects affected / exposed
    0 / 171 (0.00%)
    0 / 174 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ciprofloxacin DPI 28 Days on/off (Cipro 28) Ciprofloxacin DPI 14 Days on/off (Cipro 14) Pooled Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    51 / 171 (29.82%)
    60 / 174 (34.48%)
    55 / 174 (31.61%)
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    9 / 171 (5.26%)
    8 / 174 (4.60%)
    2 / 174 (1.15%)
         occurrences all number
    13
    16
    2
    Headache
         subjects affected / exposed
    10 / 171 (5.85%)
    10 / 174 (5.75%)
    5 / 174 (2.87%)
         occurrences all number
    15
    11
    5
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    3 / 171 (1.75%)
    7 / 174 (4.02%)
    9 / 174 (5.17%)
         occurrences all number
    3
    7
    9
    Cough
         subjects affected / exposed
    5 / 171 (2.92%)
    7 / 174 (4.02%)
    11 / 174 (6.32%)
         occurrences all number
    9
    7
    12
    Dyspnoea
         subjects affected / exposed
    4 / 171 (2.34%)
    10 / 174 (5.75%)
    3 / 174 (1.72%)
         occurrences all number
    5
    11
    6
    Haemoptysis
         subjects affected / exposed
    11 / 171 (6.43%)
    15 / 174 (8.62%)
    20 / 174 (11.49%)
         occurrences all number
    19
    22
    41
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    10 / 171 (5.85%)
    16 / 174 (9.20%)
    14 / 174 (8.05%)
         occurrences all number
    11
    19
    18
    Upper respiratory tract infection
         subjects affected / exposed
    10 / 171 (5.85%)
    8 / 174 (4.60%)
    5 / 174 (2.87%)
         occurrences all number
    13
    10
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Oct 2014
    Sample size calculation was clarified and generalized to take into account potential deviations from the original assumptions; Exclusion criterion #18 was changed to comply with an ethics committee request not to allow participation in both this study and sister study Respire 1.
    02 Sep 2015
    Deletion of one criterion for exclusion from the per-protocol analysis set (PPS) (“minimal treatment duration of 168 days”).
    29 Feb 2016
    Introduction of an additional secondary efficacy endpoint related to the frequency of exacerbations with the broader definition “event with systemic antibiotic use and worsening of at least 1 sign/symptom”; inclusion of the efficacy endpoint related to QoL-B respiratory symptoms domain score into the confirmatory testing hierarchy as secondary efficacy variable.
    15 Jul 2016
    The originally planned alpha split of 0.025 for each treatment regimen was changed to α=0.049 for the 14 days on/off regimen and α=0.001 for the 28 days on/off regimen; omission of the data extrapolation procedure for the primary analysis of exacerbation events as originally initially required by the FDA and, alternatively, inclusion of the subjects’ time on study as an offset variable in the main model.

    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.
    Occurrence of "±” in relation with geometric CV is autogenerated and cannot be deleted. ‘99999’ in the posting indicates that values were not estimated due to censored data. Decimal places were automatically truncated if last decimal equals zero.
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