Study to Evaluate the Safety and Efficacy of Ciprofloxacin (Inhaled) in Patients With Cystic Fibrosis

Study Overview
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Brief Summary
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To evaluate the change in forced expiratory volume (FEV1) from baseline to Day 28-30 between Cipro Inhale-treated and placebo-treated subjects after a 4-week treatment period.

Detailed Description
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Safety issues are addressed in the Adverse Events section.

Official Title
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Randomized, Double-blind, Placebo-controlled, Multicenter Study to Evaluate the Safety and Efficacy of Inhaled Ciprofloxacin Compared to Placebo in Subjects With Cystic Fibrosis

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: Ciprofloxacin (Cipro Inhale, BAYQ3939)
* Drug: Placebo
* Drug: Ciprofloxacin (Cipro Inhale, BAYQ3939)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects, or their legal representative(s), must have given their written informed consent to participate in the study after receiving adequate previous information and prior to any study specific procedures Children (12 - 17 years) or adults >/=18 years Documented diagnosis Cystic Fibrosis (CF): documented sweat chloride >/=60 mEq/L by quantitative pilocarpine iontophoresis test (QPIT) or nasal potential difference either homozygous for ΔF508 genetic mutation or a compound heterozygous for 2 known CF mutations and clinical findings consistent with CF Chronic colonization with P. aeruginosa defined as a positive respiratory tract culture (sputum or throat swab) within 12 months prior to screening and at screening (Note: subjects with negative culture at screening can, at the discretion of the investigator, be rescreened at a later date) Ability to perform reproducible pulmonary function tests Ability to produce sputum (noninduced) Stable pulmonary status, FEV1 >/=35% to </=75% (intraindividual variability +/-10% of absolute value). Note: The subject is not eligible for enrollment if the variability results in (or leads to) an FEV1 <35%. Room air oximetry >/=88% saturation Off antibiotics (except macrolide) and Cipro (oral) for at least 30 days prior to the administration of study drug for pulmonary exacerbation Stable regimen of standard CF treatment including chest physiotherapies and exercise regimens should not change during the 30 days prior to the administration of study drug and during the study (including macrolide administration unchanged in the previous 30 days) Subjects who are able to understand and follow instructions and who are able to participate in the study for the entire period Women who are willing to use an adequate method of contraception for 3 months after receiving the study drug. Adequate methods of contraception include vasectomy or condom use by their partners, diaphragm with spermicidal gel, coil (intrauterine device), surgical sterilization or oral contraceptive Exclusion Criteria: Findings on screening history and physical examination unrelated to CF that could potentially affect the efficacy measurements (eg, chest surgery) Subjects with colonization of Pseudomonas aeruginosa and a CIPRO MIC of >/=256 µg/ml or mg/l Burkholderia cepacia complex colonization of their respiratory tract within the past 12 months (documented by screen laboratory) Known aspergillosis (unless asymptomatic). Patients with invasive disease, ABPA with IGE > 500 mg/dL will be excluded Transaminase level >3x upper limit of normal (ULN) Massive hemoptysis (>/=300 cc or requiring blood transfusion) in the preceding 4 weeks Intravenous antibiotic treatment for pulmonary exacerbation in the past 30 days Subjects with a medical disorder, condition or history of such that would impair the subject's ability to participate or complete this study in the opinion of the investigator or the sponsor Febrile illness within 1 week before the start of the study Active treatment for nontuberculosis mycobacteria Exposure to any investigational drug within 30 days Any history of allergic reaction to fluoroquinolones or other quinolones On oral steroids >20 mg/day for longer than 14 days in the past 3 months Creatinine >/=2x ULN

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 32.50 mg Ciprofloxacin DPI (BAYQ3939)<br>32.50 mg ciprofloxacin DPI (Dry Powder for Inhalation) corresponding to 50 mg Ciprofloxacin PulmoSphere Inhalation Powder twice a day for 28 days | Drug: Ciprofloxacin (Cipro Inhale, BAYQ3939)<br>* 32.5 mg ciprofloxacin DPI corresponding to 50 mg Ciprofloxacin PulmoSphere Inhalation powder twice a day for 28 days<br>|
| Experimental: 48.75 mg Ciprofloxacin DPI (BAYQ3939)<br>48.75 mg ciprofloxacin DPI corresponding to 75 mg Ciprofloxacin PulmoSphere Inhalation Powder twice a day for 28 days | Drug: Ciprofloxacin (Cipro Inhale, BAYQ3939)<br>* 48.75 mg ciprofloxacin DPI corresponding to 75 mg Ciprofloxacin PulmoSphere Inhalation powder twice a day for 28 days (Arm 3 and Arm 4 was introduced after amendment 2)<br>|
| Placebo Comparator: Matching Placebo for 32.50 mg<br>Inhalation of placebo powder formulation matching 32.50 mg ciprofloxacin DPI twice a day for 28 days | Drug: Placebo<br>* 50 mg matching placebo powder formulation twice a day for 28 days<br>|
| Placebo Comparator: Matching Placebo for 48.75 mg<br>Inhalation of placebo powder formulation matching 48.75 mg ciprofloxacin DPI twice a day for 28 days | Drug: Placebo<br>* 75 mg matching placebo powder formulation twice a day for 28 days (Arm 3 and Arm 4 was introduced after amendment 2)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Day 28-30 | FEV1: 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). This was recorded at the site using a spirometer. The later time point minus baseline, days as planned and the last observation carried forward (LOCF) used. | Baseline and End of treatment (Day 28-30) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in FEV1 at Visits 4, 5, and Follow-up Visits 8 and 9 | FEV1: 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). This was recorded at the site using a spirometer. The later time point minus baseline, days as planned and the last observation carried forward (LOCF) used. | Baseline and Visit 4 (Day 7-9), Visit 5 (Day 14-16), Visit 8 (Day 41-45), and Visit 9 (Day 56 -60). | 
| Change From Baseline in P. Aeruginosa Density in the Sputum at Visits 4, 5, 7, 8 and 9 | Density of P. aeruginosa in the sputum is expressed as log10 of colony forming units (CFU)/gram (g). The later time point minus baseline, days as planned and the last observation carried forward (LOCF) used. | Baseline and Visit 4 (Day 7-9), Visit 5 (Day 14-16), Visit 7 (Day 28-30), Visit 8 (Day 41-45), and Visit 9 (Day 56 -60). | 
| Time to First Pulmonary Exacerbation Requiring Intervention | Pulmonary exacerbations: Assessment of pulmonary exacerbation was conducted by the treating physician as part of the physical examination. Pulmonary exacerbation was defined by chest examination findings and any or all of the following symptoms: decreased exercise tolerance, increased cough, increased sputum/cough congestion, school or work absenteeism, increased adventitial sounds on the lung examination, and decreased appetite. | Up to visit 9 (Day 56-60) | 
| Change From Baseline in Forced Vital Capacity (FVC) at Visits 4, 5, 7, 8 and 9 | FVC: The maximal volume of air exhaled with maximally forced effort from a maximal inspiration, ie, vital capacity performed with a maximally forced expiratory effort expressed in liters at BTPS (body temperature and ambient pressure saturated with water vapor). The later time point minus baseline, days as planned and the last observation carried forward (LOCF) used. | Baseline and Visit 4 (Day 7-9), Visit 5 (Day 14-16), Visit 7 (Day 28-30), Visit 8 (Day 41-45), and Visit 9 (Day 56 -60). | 
| Change From Baseline in Forced Expiratory Flow (FEF 25-75%) at Visits 4, 5, 7, 8 and 9 | FEF 25-75% (also known as the maximum midexpiratory flow [MMEF]): The mean forced expiration flow over the middle half of the forced vital capacity (FVC). It was taken from the blow with the largest sum of FEV1 and FVC. The later time point minus baseline, days as planned and the last observation carried forward (LOCF) used. | Baseline and Visit 4 (Day 7-9), Visit 5 (Day 14-16), Visit 7 (Day 28-30), Visit 8 (Day 41-45), and Visit 9 (Day 56 -60). | 
| Number of Participants Developing Ciprofloxacin-resistant Mucoid P.Aeruginosa Isolates | Susceptibility and resistance assessment of a bacterial isolate was performed using the established Food and Drug Administration (FDA) susceptibility criteria for ciprofloxacin. The susceptibility criteria in mg/L are ≤1 for organisms Enterobacteriaciae, P. aeruginosa, Staphylococcus species and S. pneumoniae. The susceptible bacterial species likely responds to typical doses of ciprofloxacin. The resistance criteria for ciprofloxacin in mg/L are ≥4 mg/L for the same organisms. Resistance indicates that the bacteria is less likely to respond to typical doses of ciprofloxacin therapy. | Baseline and up to visit 9 (day 56-60) | 
| Number of Participants Developing Ciprofloxacin-resistant Non-mucoid P.Aeruginosa Isolates | Susceptibility and resistance assessment of a bacterial isolate was performed using the established Food and Drug Administration (FDA) susceptibility criteria for ciprofloxacin. The susceptibility criteria in mg/L are ≤1 for organisms Enterobacteriaciae, P. aeruginosa, Staphylococcus species and S. pneumoniae. The susceptible bacterial species likely responds to typical doses of ciprofloxacin. The resistance criteria for ciprofloxacin in mg/L are ≥4 mg/L for the same organisms. Resistance indicates that the bacteria is less likely to respond to typical doses of ciprofloxacin therapy. | Baseline and up to visit 9 (day 56-60) | 
| Effect of Ciprofloxacin DPI Treatment on Quality of Life Measured by Cystic Fibrosis Quality of Life Questionnaire Revised (CFQ-R), Respiratory Scale | The CF quality of life questionnaire revised (CFQ-R), a validated disease-specific instrument that measures health-related quality of life (HRQOL) for adolescents and adults with cystic fibrosis (CF). It is self-administered and consists of 44 items, divided into 12 generic and disease-specific scales. The scale includes physical functioning, role, vitality, emotional functioning, social functioning, body image, eating disturbances, treatment burden, health perceptions, weight, respiratory symptoms, and digestive symptoms. Scale range: 0 to 100 (maximum). Better outcome with higher values. | Baseline and Visit 7 (Day 28-30) and Visit 9 (Day 56 -60) | 
| Plasma Concentrations of Ciprofloxacin From Selected Participants During Treatment | Plasma concentrations measured using validated high pressure liquid chromatography-mass specroscopy/mass spectroscopy (HPLC-MS/MS) methods in selected patients at predefined time windows to contribute pharmacokinetic (PK) information for an inter-study population PK evaluation. Sampling window for Plasma: Predose (trough level), <15 min, 2.0 - 2.5 hour, and 4.0 - 7.0 hours after the end of inhalation. Number of samples vary at different time points. | Up to visit 7 (Day 28-30) | 
| Sputum Concentrations of Ciprofloxacin From Selected Participants During Treatment | Sputum concentrations measured using validated HPLC-MS/MS methods in selected patients to contribute kinetic information for an inter-study population sputum kinetic evaluation. Number of samples vary at different time points. | Up to visit 7 (Day 28-30) | 
| Number of Participants With the Occurrence of Drug Induced Bronchospasms | Bronchospasm reported as adverse event: Bronchospasm defined as >=15% drop in FEV1, and may also include allergic and excercise-induced bronchospasm. Drug-induced bronchospasm: Treatment-emergent bronchospasm was defined as >=15% drop in FEV1 in the ITT/safety population. Note: One of the bronchospasm events was considered a serious adverse event, and it was not included under other adverse events. A sum of bronchospasm events was 1+6=7. | Up to visit 9 (Day 56-60) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ciprofloxacin, cystic fibrosis, sweat test, pulmonary function test