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

Study Description

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Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Cystic Fibrosis	Drug: Ciprofloxacin (Cipro Inhale, BAYQ3939); Drug: Placebo	Phase 2

Detailed Description:

Safety issues are addressed in the Adverse Events section.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	288 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	Randomized, Double-blind, Placebo-controlled, Multicenter Study to Evaluate the Safety and Efficacy of Inhaled Ciprofloxacin Compared to Placebo in Subjects With Cystic Fibrosis
Study Start Date :	May 2008
Actual Primary Completion Date :	January 2011
Actual Study Completion Date :	January 2011

Arms and Interventions

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

Outcome Measures

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Primary Outcome Measures :

1. Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Day 28‑30 [ Time Frame: Baseline and End of treatment (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.

Secondary Outcome Measures :

1. Change From Baseline in FEV1 at Visits 4, 5, and Follow-up Visits 8 and 9 [ Time Frame: Baseline and Visit 4 (Day 7-9), Visit 5 (Day 14-16), Visit 8 (Day 41-45), and Visit 9 (Day 56 -60). ]
   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.
2. Change From Baseline in P. Aeruginosa Density in the Sputum at Visits 4, 5, 7, 8 and 9 [ Time Frame: 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). ]
   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.
3. Time to First Pulmonary Exacerbation Requiring Intervention [ Time Frame: Up to visit 9 (Day 56-60) ]
   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.
4. Change From Baseline in Forced Vital Capacity (FVC) at Visits 4, 5, 7, 8 and 9 [ Time Frame: 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). ]
   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.
5. Change From Baseline in Forced Expiratory Flow (FEF 25-75%) at Visits 4, 5, 7, 8 and 9 [ Time Frame: 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). ]
   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.
6. Number of Participants Developing Ciprofloxacin-resistant Mucoid P.Aeruginosa Isolates [ Time Frame: Baseline and up to visit 9 (day 56-60) ]
   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.
7. Number of Participants Developing Ciprofloxacin-resistant Non-mucoid P.Aeruginosa Isolates [ Time Frame: Baseline and up to visit 9 (day 56-60) ]
   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.
8. Effect of Ciprofloxacin DPI Treatment on Quality of Life Measured by Cystic Fibrosis Quality of Life Questionnaire Revised (CFQ-R), Respiratory Scale [ Time Frame: Baseline and Visit 7 (Day 28-30) and Visit 9 (Day 56 -60) ]
   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.
9. Plasma Concentrations of Ciprofloxacin From Selected Participants During Treatment [ Time Frame: Up to visit 7 (Day 28-30) ]
   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.
10. Sputum Concentrations of Ciprofloxacin From Selected Participants During Treatment [ Time Frame: Up to visit 7 (Day 28-30) ]
    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.
11. Number of Participants With the Occurrence of Drug Induced Bronchospasms [ Time Frame: Up to visit 9 (Day 56-60) ]
    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.

Eligibility Criteria

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Ages Eligible for Study:	12 Years and older (Child, Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

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Locations

United States, Arizona
Phoenix, Arizona, United States, 85016
Tucson, Arizona, United States, 85724
United States, Arkansas
Little Rock, Arkansas, United States, 72205
United States, California
Los Angeles, California, United States, 90027
Los Angeles, California, United States, 90033
Los Angeles, California, United States, 90048
Orange, California, United States, 92868
San Diego, California, United States, 92123-4282
San Francisco, California, United States, 94143
Ventura, California, United States, 93003
United States, Colorado
Aurora, Colorado, United States, 80045
United States, Connecticut
Hartford, Connecticut, United States, 06102
New Haven, Connecticut, United States, 06520
United States, Florida
Jacksonville, Florida, United States, 32207
Miami, Florida, United States, 33136
Orlando, Florida, United States, 32801
Orlando, Florida, United States, 32803
Orlando, Florida, United States, 32806
United States, Georgia
Augusta, Georgia, United States, 30912-4005
United States, Illinois
Chicago, Illinois, United States, 60612
Chicago, Illinois, United States, 60614
Glenview, Illinois, United States, 60025
Maywood, Illinois, United States, 60153
United States, Indiana
Indianapolis, Indiana, United States, 46202
United States, Iowa
Iowa city, Iowa, United States, 52242-1089
United States, Kentucky
Lexington, Kentucky, United States, 40536-0284
Louisville, Kentucky, United States, 40207
United States, Massachusetts
Boston, Massachusetts, United States, 02111
Boston, Massachusetts, United States, 02115
United States, Michigan
Ann Arbor, Michigan, United States, 48109
Kalamazoo, Michigan, United States, 49007
United States, Mississippi
Jackson, Mississippi, United States, 39216
United States, Nevada
Las Vegas, Nevada, United States, 89107
United States, New Jersey
Livingston, New Jersey, United States, 07039
Long Branch, New Jersey, United States, 07740
Morristown, New Jersey, United States, 07962
Somerville, New Jersey, United States, 08876
United States, New York
Albany, New York, United States, 12208
New Hyde Park, New York, United States, 11040
Valhalla, New York, United States, 10595
United States, North Carolina
Durham, North Carolina, United States, 27710
United States, Ohio
Akron, Ohio, United States, 44308-1062
Cincinnati, Ohio, United States, 45229-3039
Toledo, Ohio, United States, 43606
United States, Oklahoma
Oklahoma City, Oklahoma, United States, 73104
Oklahoma City, Oklahoma, United States, 73112
Tulsa, Oklahoma, United States, 74145
United States, Pennsylvania
Hershey, Pennsylvania, United States, 17033-0850
Philadelphia, Pennsylvania, United States, 19104-4283
Philadelphia, Pennsylvania, United States, 19134
United States, South Carolina
Charleston, South Carolina, United States, 29425
United States, Tennessee
Knoxville, Tennessee, United States, 37916
United States, Texas
Austin, Texas, United States, 78723
San Antonio, Texas, United States, 78212
United States, Utah
Salt Lake City, Utah, United States, 84132
United States, Virginia
Charlottesville, Virginia, United States, 22908
United States, Washington
Seattle, Washington, United States, 98105
United States, Wisconsin
Madison, Wisconsin, United States, 53792
Australia, Queensland
Brisbane, Queensland, Australia, 4029
Chermside, Queensland, Australia, 4032
South Brisbane, Queensland, Australia, 4101
Australia, South Australia
Adelaide, South Australia, Australia, 5000
Australia, Victoria
Clayton, Victoria, Australia, 3168
Parkville, Victoria, Australia, 3052
Australia, Western Australia
Nedlands, Western Australia, Australia, 6009
Canada, Newfoundland and Labrador
St. John's, Newfoundland and Labrador, Canada, A1B 3V6
Canada, Ontario
Hamilton, Ontario, Canada, L8S 4J9
London, Ontario, Canada, N6A 5B8
Canada, Quebec
Montreal, Quebec, Canada, H2X 2P4
Denmark
Copenhagen, Denmark, 2100
Germany
München, Bayern, Germany, 80336
Frankfurt, Hessen, Germany, 60590
Leipzig, Sachsen, Germany, 04103
Berlin, Germany, 12200
Israel
Haifa, Israel
Jerusalem, Israel
Petach Tikva, Israel
Tel Hashomer, Israel
Norway
Oslo, Norway, 0407
Sweden
Göteborg, Sweden, 416 85
Lund, Sweden, 221 85
Uppsala, Sweden, 751 85
United Kingdom
Cambridge, Cambridgeshire, United Kingdom, CB3 8RE
Southampton, Hampshire, United Kingdom, SO16 6YD
Belfast, North Ireland, United Kingdom, BT12 7AB
Birmingham, West Midlands, United Kingdom, B9 5SS

Sponsors and Collaborators

Bayer

Novartis

Investigators

Study Director:	Bayer Study Director	Bayer

More Information

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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Dorkin HL, Staab D, Operschall E, Alder J, Criollo M. Ciprofloxacin DPI: a randomised, placebo-controlled, phase IIb efficacy and safety study on cystic fibrosis. BMJ Open Respir Res. 2015 Dec 2;2(1):e000100. doi: 10.1136/bmjresp-2015-000100. eCollection 2015.

Responsible Party:	Bayer
ClinicalTrials.gov Identifier:	NCT00645788 History of Changes
Other Study ID Numbers:	12429; 2008-008314-40 ( EudraCT Number )
First Posted:	March 28, 2008
Results First Posted:	July 3, 2012
Last Update Posted:	June 9, 2014
Last Verified:	May 2014

Keywords provided by Bayer:

Ciprofloxacin; cystic fibrosis; sweat test; pulmonary function test

Additional relevant MeSH terms:

Fibrosis; Cystic Fibrosis; Pathologic Processes; Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Infant, Newborn, Diseases; Ciprofloxacin	Anti-Bacterial Agents; Anti-Infective Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Cytochrome P-450 CYP1A2 Inhibitors; Cytochrome P-450 Enzyme Inhibitors