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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
    		 2011-004208-39
    Trial protocol
    		 DE   ES   GB   IT   DK   FR   LV   SK  
    Global end of trial date
    09 Mar 2016

    Results information
    Results version number
    		 v4(current)
    This version publication date
    24 Dec 2017
    First version publication date
    11 Mar 2017
    Other versions
    		 v1 , v2 , v3
    Version creation reason
    • Correction of full data set
    update in SAE section

    Trial information

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    Trial identification
    Sponsor protocol code
    BAYQ3939/15625
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01764841
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, D-51368 Leverkusen, Germany,
    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
    09 Mar 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Mar 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary objectives: 1) To evaluate the efficacy of ciprofloxacin dry powder for inhalation (DPI) administered twice daily (BID) intermittently for 28 days on/off treatment or 14 days on/off treatment to prolong the time to first exacerbation requiring an intervention with systemic antibiotics in subjects with non–cystic fibrosis bronchiectasis (non-CF BE) within 48 weeks after start of treatment. 2) To evaluate the efficacy of ciprofloxacin DPI administered BID intermittently for 28 days on/off treatment or 14 days on/off treatment in reducing the frequency of pulmonary exacerbation requiring an intervention with systemic antibiotics in subjects with non–CF BE within 48 weeks after start of treatment. The tests for the efficacy variables will be performed hierarchically. The comparisons ciprofloxacin DPI vs. placebo (matching or pooled according to statistical analysis plan defined for EU registration) will be performed in parallel for the regimen 28 days on/off and 14 days on/off.
    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
    02 May 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Slovakia: 2
    Country: Number of subjects enrolled
    Spain: 49
    Country: Number of subjects enrolled
    United Kingdom: 27
    Country: Number of subjects enrolled
    United States: 44
    Country: Number of subjects enrolled
    Argentina: 6
    Country: Number of subjects enrolled
    Australia: 52
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    France: 14
    Country: Number of subjects enrolled
    Germany: 47
    Country: Number of subjects enrolled
    Israel: 53
    Country: Number of subjects enrolled
    Italy: 21
    Country: Number of subjects enrolled
    Japan: 33
    Country: Number of subjects enrolled
    Latvia: 16
    Country: Number of subjects enrolled
    New Zealand: 51
    Worldwide total number of subjects
    416
    EEA total number of subjects
    177
    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)
    166
    From 65 to 84 years
    243
    85 years and over
    7

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study was conducted at 124 study centers in 14 countries (Argentina, Australia, Denmark, France, Germany, Israel, Italy, Japan, Latvia, New Zealand, Slovakia, Spain, UK and US) between 02 May 2013 (first subject first visit) and 09 March 2016 (last subject last visit).

    Pre-assignment
    Screening details
    		 Overall 902 subjects were screened, of them 486 were screen failures, and 416 were randomized, out of which 414 subjects were assigned to the treatment. One subject from Ciprofloxacin 14 Days on/off group and one subject from Placebo 28 Days on/off group did not receive the study treatment after initial screening.

    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, 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 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).
    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
    Subjects received 32.5 mg ciprofloxacin hydrated (corresponding to 50 mg dry powder) administered BID (every 12 hours) using T-326 powder inhaler device.

    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
    Subjects received 32.5 mg ciprofloxacin hydrated (corresponding to 50 mg dry powder) administered BID (every 12 hours) using T-326 powder inhaler device.

    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
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Subjects received placebo matched to ciprofloxacin 32.5 mg powder (containing 40 mg dry powder) administered BID (every 12 hours) using T-326 powder inhaler device.

    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
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Subjects received placebo matched to ciprofloxacin 32.5 mg powder (containing 40 mg dry powder) administered BID (every 12 hours) using T-326 powder inhaler device.

    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
    141
    137
    70
    68
    Treated
    141
    136
    69
    68
    Completed
    118
    111
    56
    49
    Not completed
    23
    26
    14
    19
         Consent withdrawn by subject
    16
    24
    11
    15
         Logistical Difficulties
    -
    1
    -
    -
         Death
    3
    -
    1
    4
         Protocol Violation
    -
    1
    -
    -
         Lost to follow-up
    3
    -
    1
    -
         No Follow Up
    1
    -
    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 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
    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
    		 141 137 70 68 416
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.2 ( 12.1 ) 65.2 ( 13.5 ) 64 ( 13.5 ) 65.5 ( 12.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 101 88 52 44 285
        Male
    		 40 49 18 24 131
    Saint George's Respiratory Questionnaire (SGRQ) Symptoms Component Score (n=135, 129, 67, 66)
    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)
    		 60.72 ( 19.47 ) 52.51 ( 21.48 ) 55.52 ( 22.07 ) 58.72 ( 20.4 ) -
    QoL-B Respiratory Symptoms Domain Score (n= 128, 120, 63, 65)
    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)
    		 53.01 ( 18.71 ) 57.69 ( 18.72 ) 55.82 ( 18.04 ) 50.67 ( 19.59 ) -
    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)
    		 1.521 ( 0.521 ) 1.528 ( 0.625 ) 1.577 ( 0.651 ) 1.468 ( 0.574 ) -

    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 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
    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
    FAS (N=416) included subjects who were randomized.

    Subject analysis set title
    Safety analysis set (SAF)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    SAF (N=414) 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 (N=138) 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 subjects with exacerbation events with worsening of at least three signs/symptoms over 48 weeks

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    End point title
    		 Number of subjects 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
    141 [1]
    137 [2]
    70 [3]
    68 [4]
    Units: subjects with exacerbation events
        Number of exacerbations: 0
    74
    84
    33
    26
        Number of exacerbations: 1
    39
    33
    27
    23
        Number of exacerbations: 2
    13
    11
    4
    12
        Number of exacerbations: 3
    12
    6
    4
    4
        Number of exacerbations: 4
    1
    2
    2
    3
        Number of exacerbations: 5
    1
    1
    0
    0
        Number of exacerbations: 6
    1
    0
    0
    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
    Placebo 28 Days on/off (Placebo 28) v Ciprofloxacin DPI 28 Days on/off (Cipro 28)
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8946
    Method
    		 Poisson regression
    Parameter type
    		 Incidence Rate Ratio
    Point estimate
    0.9757
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.6434
         upper limit
    		 1.4796
    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
    205
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0061
    Method
    		 Poisson regression
    Parameter type
    		 Incidence Rate Ratio
    Point estimate
    0.6076
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.4043
         upper limit
    		 0.9131

    Secondary: Time to First Exacerbation Event Within 48 Weeks

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    End point title
    		 Time to First Exacerbation Event Within 48 Weeks [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) Ciprofloxacin DPI 14 Days on/off (Cipro 14) Pooled Placebo
    Number of subjects analysed
    141 [6]
    137 [7]
    138 [8]
    Units: Days
        median (confidence interval 97.5%)
    336 (206 to 99999)
    99999 (290 to 99999)
    186 (136 to 282)
    Notes
    [6] - FAS
    [7] - FAS
    [8] - FAS
    Statistical analysis title
    		 Cipro 28 vs Pooled Placebo
    Statistical analysis description
    The hazard ratio for time to first exacerbation event within 48 weeks and 97.5% CI was calculated by using Cox proportional hazards model by comparison of Cipro 28/Pooled Placebo reporting groups. P-value was analysed using Wald-type test.
    Comparison groups
    Ciprofloxacin DPI 28 Days on/off (Cipro 28) v Pooled Placebo
    Number of subjects included in analysis
    279
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.065
    Method
    		 Wald-type test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.7331
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.5027
         upper limit
    		 1.069
    Statistical analysis title
    		 Cipro 14 vs Pooled Placebo
    Statistical analysis description
    The hazard ratio for time to first exacerbation event within 48 weeks and 97.5% CI was calculated by using Cox proportional hazards model by comparison of Cipro 14/Pooled Placebo reporting groups. P-value was analysed using Wald-type test.
    Comparison groups
    Ciprofloxacin DPI 14 Days on/off (Cipro 14) v Pooled Placebo
    Number of subjects included in analysis
    275
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0005
    Method
    		 Wald-type test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.5333
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.3568
         upper limit
    		 0.7971

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

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    End point title
    		 Number of subjects 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
    141 [9]
    137 [10]
    70 [11]
    68 [12]
    Units: Subjects with exacerbation events
        Number of exacerbations: 0
    58
    68
    25
    21
        Number of exacerbations: 1
    47
    42
    26
    17
        Number of exacerbations: 2
    12
    15
    11
    20
        Number of exacerbations: 3
    14
    5
    5
    6
        Number of exacerbations: 4
    4
    2
    3
    2
        Number of exacerbations: 5
    4
    3
    0
    2
        Number of exacerbations: 6
    2
    2
    0
    0
    Notes
    [9] - FAS
    [10] - FAS
    [11] - FAS
    [12] - 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
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8628
    Method
    		 Wald-type test
    Parameter type
    		 Incidence rate ratio
    Point estimate
    0.9715
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.6674
         upper limit
    		 1.4141
    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
    205
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.011
    Method
    		 Wald-type test
    Parameter type
    		 Incidence rate ratio
    Point estimate
    0.6573
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.4542
         upper limit
    		 0.9513

    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) [13]
    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 subject at baseline. There was no imputation for subjects who discontinued the study prematurely.
    End point type
    Secondary
    End point timeframe
    End of treatment (Week 44/46)
    Notes
    [13] - 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
    141 [14]
    137 [15]
    138 [16]
    Units: Percentage of subjects
    number (not applicable)
        No
    39
    26.3
    33.3
        Yes
    24.1
    28.5
    16.7
    Notes
    [14] - FAS
    [15] - FAS
    [16] - FAS
    Statistical analysis title
    		 Cipro 28 vs Pooled Placebo
    Statistical analysis description
    A Cochran-Mantel-Haenszel test was used to analyse the P-value by comparing cipro 28 and pooled placebo treatments with no imputation method.
    Comparison groups
    Ciprofloxacin DPI 28 Days on/off (Cipro 28) v Pooled Placebo
    Number of subjects included in analysis
    279
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 = 0.6723
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [17] - Odds ratio (OR) =1.162
    Statistical analysis title
    		 Cipro 14 vs Pooled Placebo
    Statistical analysis description
    A Cochran-Mantel-Haenszel test was used to analyse the P-value by comparing cipro 14 and pooled placebo treatments with no imputation method.
    Comparison groups
    Ciprofloxacin DPI 14 Days on/off (Cipro 14) v Pooled Placebo
    Number of subjects included in analysis
    275
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [18]
    P-value
    		 = 0.0182
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [18] - Odds ratio (OR) = 2.35

    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, 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
    110 [19]
    97 [20]
    46 [21]
    43 [22]
    Units: score on a scale
        arithmetic mean (standard deviation)
    -8.17 ( 22.92 )
    -7.2 ( 20.41 )
    -4.23 ( 19.55 )
    2.78 ( 16.16 )
    Attachments
    		 Untitled (Filename: Statistical Analysis Cipro 28 vs Pooled and Cipro 14 vs Pooled_SGRQ.docx)
    Notes
    [19] - FAS with subjects evaluable for this endpoint.
    [20] - FAS with subjects evaluable for this endpoint.
    [21] - FAS with subjects evaluable for this endpoint.
    [22] - FAS with subjects evaluable for this endpoint.
    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 subjects 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
    141 [24]
    137 [25]
    138 [26]
    Units: Percentage of subjects
    number (not applicable)
        No
    60.3
    49.6
    42.8
        Yes
    3.5
    5.1
    8
    Notes
    [24] - FAS
    [25] - FAS
    [26] - FAS
    Statistical analysis title
    		 Cipro 28 vs Pooled Placebo
    Statistical analysis description
    Cochran-Mantel-Haenszel model was used as the confirmatory analysis to test for differences in the occurrence of new pathogens present at end of treatment between the cipro 28 and pooled placebo treatment groups with no imputation method.
    Comparison groups
    Ciprofloxacin DPI 28 Days on/off (Cipro 28) v Pooled Placebo
    Number of subjects included in analysis
    279
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [27]
    P-value
    		 = 0.0582
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [27] - Odds ratio (OR) = 0.363
    Statistical analysis title
    		 Cipro 14 vs Pooled Placebo
    Statistical analysis description
    Cochran-Mantel-Haenszel model was used as the confirmatory analysis to test for differences in the occurrence of new pathogens present at end of treatment between the cipro 14 and pooled placebo treatment groups with no imputation method.
    Comparison groups
    Ciprofloxacin DPI 14 Days on/off (Cipro 14) v Pooled Placebo
    Number of subjects included in analysis
    275
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [28]
    P-value
    		 = 0.2569
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [28] - Odds ratio (OR) = 0.557

    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, 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
    106 [29]
    89 [30]
    45 [31]
    42 [32]
    Units: score on a scale
        arithmetic mean (standard deviation)
    7.7 ( 18.5 )
    6.72 ( 17.9 )
    8.22 ( 16.74 )
    4.45 ( 17.78 )
    Notes
    [29] - FAS with subjects evaluable for this endpoint.
    [30] - FAS with subjects evaluable for this endpoint.
    [31] - FAS with subjects evaluable for this endpoint.
    [32] - FAS with subjects evaluable for this endpoint.
    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, 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
    112 [33]
    98 [34]
    45 [35]
    41 [36]
    Units: liter
        arithmetic mean (standard deviation)
    -0.012 ( 0.149 )
    -0.026 ( 0.226 )
    0.024 ( 0.344 )
    0.022 ( 0.352 )
    Notes
    [33] - FAS with subjects evaluable for this endpoint.
    [34] - FAS with subjects evaluable for this endpoint.
    [35] - FAS with subjects evaluable for this endpoint.
    [36] - FAS with subjects evaluable for this endpoint.
    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
    18.1
    Reporting groups
    Reporting group title
    Ciprofloxacin DPI 28 Days on/off
    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
    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 day 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).

    Reporting group title
    Ciprofloxacin DPI 14 Days on/off
    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).

    Serious adverse events
    		 Ciprofloxacin DPI 28 Days on/off Pooled Placebo Ciprofloxacin DPI 14 Days on/off
    Total subjects affected by serious adverse events
         subjects affected / exposed
    29 / 141 (20.57%)
    32 / 137 (23.36%)
    23 / 136 (16.91%)
         number of deaths (all causes)
    3
    5
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 137 (0.73%)
    0 / 136 (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
    Breast cancer
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 137 (0.00%)
    0 / 136 (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
    Malignant melanoma
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 137 (0.73%)
    0 / 136 (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
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 137 (0.73%)
    0 / 136 (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
    Thyroid cancer recurrent
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Invasive lobular breast carcinoma
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 137 (0.73%)
    0 / 136 (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
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 137 (0.73%)
    0 / 136 (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
    General disorders and administration site conditions
    Strangulated hernia
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral swelling
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 137 (0.00%)
    0 / 136 (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
    General physical health deterioration
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypogammaglobulinaemia
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 137 (0.00%)
    0 / 136 (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
    Prostatic haemorrhage
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         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, thoracic and mediastinal disorders
    Bronchiectasis
         subjects affected / exposed
    16 / 141 (11.35%)
    17 / 137 (12.41%)
    8 / 136 (5.88%)
         occurrences causally related to treatment / all
    0 / 20
    0 / 19
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 137 (0.00%)
    0 / 136 (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
    Dyspnoea
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 137 (0.00%)
    0 / 136 (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
    Epistaxis
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 137 (0.73%)
    0 / 136 (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
    Haemoptysis
         subjects affected / exposed
    2 / 141 (1.42%)
    2 / 137 (1.46%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 137 (0.73%)
    0 / 136 (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
    Pleural effusion
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 137 (0.73%)
    0 / 136 (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
    Pneumonia aspiration
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 137 (0.00%)
    0 / 136 (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
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 137 (0.73%)
    0 / 136 (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
    Respiratory failure
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 137 (0.73%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Influenza A virus test positive
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 137 (0.00%)
    0 / 136 (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
    Injury, poisoning and procedural complications
    Clavicle fracture
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Complications of transplant surgery
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 137 (0.73%)
    0 / 136 (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
    Femoral neck fracture
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urethral stricture traumatic
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 137 (0.73%)
    0 / 136 (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
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 137 (0.00%)
    0 / 136 (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
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 137 (0.00%)
    0 / 136 (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
    Cardiac failure
         subjects affected / exposed
    0 / 141 (0.00%)
    2 / 137 (1.46%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 137 (0.73%)
    0 / 136 (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
    Cardiac failure congestive
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 137 (0.73%)
    0 / 136 (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
    Cor pulmonale
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 137 (0.00%)
    0 / 136 (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
    Mitral valve incompetence
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral atrophy
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 137 (0.73%)
    0 / 136 (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
    Cerebrovascular accident
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Normal pressure hydrocephalus
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 137 (0.73%)
    0 / 136 (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
    Paraesthesia
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 137 (0.00%)
    0 / 136 (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
    Syncope
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 137 (0.73%)
    0 / 136 (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
    Transient global amnesia
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 137 (0.73%)
    0 / 136 (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
    Anaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 137 (0.73%)
    0 / 136 (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
    Angle closure glaucoma
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 137 (0.00%)
    0 / 136 (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
    Retinal vasculitis
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 137 (0.73%)
    0 / 136 (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
    Gastric ulcer haemorrhage
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 137 (0.73%)
    0 / 136 (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
    Portal hypertension
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 137 (0.73%)
    0 / 136 (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
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urethral stenosis
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 137 (0.73%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 137 (0.73%)
    0 / 136 (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
    Fracture nonunion
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 137 (0.73%)
    0 / 136 (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
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 137 (0.00%)
    0 / 136 (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
    Infections and infestations
    Bronchiolitis
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 137 (0.00%)
    0 / 136 (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
    Cellulitis
         subjects affected / exposed
    1 / 141 (0.71%)
    1 / 137 (0.73%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis clostridial
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 137 (0.73%)
    0 / 136 (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
    Influenza
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 137 (0.73%)
    0 / 136 (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
    Pathogen resistance
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 141 (2.84%)
    5 / 137 (3.65%)
    4 / 136 (2.94%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 137 (0.00%)
    0 / 136 (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
    2 / 141 (1.42%)
    1 / 137 (0.73%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyometra
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 137 (0.00%)
    0 / 136 (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
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         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 Pooled Placebo Ciprofloxacin DPI 14 Days on/off
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    74 / 141 (52.48%)
    62 / 137 (45.26%)
    83 / 136 (61.03%)
    Investigations
    Aspergillus test positive
         subjects affected / exposed
    6 / 141 (4.26%)
    0 / 137 (0.00%)
    7 / 136 (5.15%)
         occurrences all number
    6
    0
    8
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 141 (1.42%)
    1 / 137 (0.73%)
    7 / 136 (5.15%)
         occurrences all number
    2
    1
    7
    Headache
         subjects affected / exposed
    11 / 141 (7.80%)
    4 / 137 (2.92%)
    14 / 136 (10.29%)
         occurrences all number
    14
    6
    16
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    5 / 141 (3.55%)
    7 / 137 (5.11%)
    7 / 136 (5.15%)
         occurrences all number
    5
    7
    8
    Fatigue
         subjects affected / exposed
    6 / 141 (4.26%)
    3 / 137 (2.19%)
    12 / 136 (8.82%)
         occurrences all number
    6
    3
    14
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    7 / 141 (4.96%)
    5 / 137 (3.65%)
    9 / 136 (6.62%)
         occurrences all number
    7
    5
    11
    Nausea
         subjects affected / exposed
    5 / 141 (3.55%)
    7 / 137 (5.11%)
    10 / 136 (7.35%)
         occurrences all number
    5
    7
    11
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    6 / 141 (4.26%)
    10 / 137 (7.30%)
    7 / 136 (5.15%)
         occurrences all number
    7
    13
    13
    Cough
         subjects affected / exposed
    15 / 141 (10.64%)
    9 / 137 (6.57%)
    13 / 136 (9.56%)
         occurrences all number
    18
    12
    18
    Dyspnoea
         subjects affected / exposed
    15 / 141 (10.64%)
    9 / 137 (6.57%)
    16 / 136 (11.76%)
         occurrences all number
    21
    11
    26
    Haemoptysis
         subjects affected / exposed
    15 / 141 (10.64%)
    8 / 137 (5.84%)
    16 / 136 (11.76%)
         occurrences all number
    34
    10
    32
    Sputum increased
         subjects affected / exposed
    8 / 141 (5.67%)
    3 / 137 (2.19%)
    6 / 136 (4.41%)
         occurrences all number
    9
    4
    8
    Oropharyngeal pain
         subjects affected / exposed
    3 / 141 (2.13%)
    5 / 137 (3.65%)
    7 / 136 (5.15%)
         occurrences all number
    3
    5
    9
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    10 / 141 (7.09%)
    6 / 137 (4.38%)
    9 / 136 (6.62%)
         occurrences all number
    13
    6
    10
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    15 / 141 (10.64%)
    10 / 137 (7.30%)
    16 / 136 (11.76%)
         occurrences all number
    20
    15
    21
    Sinusitis
         subjects affected / exposed
    4 / 141 (2.84%)
    8 / 137 (5.84%)
    10 / 136 (7.35%)
         occurrences all number
    5
    10
    12
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 141 (2.84%)
    10 / 137 (7.30%)
    9 / 136 (6.62%)
         occurrences all number
    5
    13
    9

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Feb 2013
    Following modifications were done in this amendment: -Pregnancy tests before each cycles were accommodated by phone calls for more frequent AE inquiries. -Follow-up time was harmonized to 8 weeks after last dose for both regimens were improved. -Separate statistical analysis plan were to be provided for European Medicines Agency and Food and Drug Administration. -The questionnaire QOL-B is now available in all participating countries. Inclusion and exclusion criteria were checked, added, or rephrased.
    28 Oct 2013
    Following modifications were done in this amendment: -Harmonized several passages of the protocol with that of the protocol of the twin study. -Inclusion only after proven and documented diagnosis of non-CF idiopathic or post-infectious bronchiectasis by high resolution computed tomography (HRCT) was changed into diagnosis “by computer tomography (CT)" -In the 14 days on/off regimen the urine pregnancy testing was deleted from flow chart at Visit 7 and 11.
    18 Aug 2014
    Following modifications were done in this amendment: -Adjusted the sample size. -The criteria or exacerbations that qualify for the primary endpoint of this study were clarified.
    24 Aug 2015
    Deleted one criterion for exclusion from the per-protocol analysis set (PPS) (minimal treatment duration of 168 days).
    16 Dec 2015
    Following modifications were done in this amendment: -Introduced an additional secondary efficacy endpoint (i.e. exacerbation events are defined as events with systemic antibiotic use and worsening of at least one sign/symptom). -Inclusion of the patient reported outcome (PRO) endpoint QoL-B (questionnaire’s respiratory symptom domain) into the panel of secondary (confirmatory) efficacy endpoints (from previously “other” efficacy variable). -Clarification of the observational period for the endpoint time to first exacerbation qualifying as event according to the protocol as “within 48 weeks after start of treatment”.

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

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