Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12609000544279
Ethics application status
Approved
Date submitted
12/06/2009
Date registered
7/07/2009
Date last updated
7/07/2009
Type of registration
Retrospectively registered

Titles & IDs
Public title
A single dose, 3-way cross-over study comparing the safety, tolerability and pharmacokinetics of two inhaled Liposomal Ciprofloxacin Hydrochloride (HCl) for Inhalation formulations in two different nebulizers in healthy adults, with single dose assessment in subjects with non-Cystic Fibrosis (CF) bronchiectasis.
Scientific title
A single dose, 3-way cross-over study comparing the safety, tolerability and pharmacokinetics of two inhaled Liposomal Ciprofloxacin Hydochloride (HCl) for Inhalation formulations in two different nebulizers in healthy adults, with single dose assessment in subjects with non-Cystic Fibrosis (CF) bronchiectasis.
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Non-Cystic Fibrosis (CF) bronchiectasis 236982 0
Condition category
Condition code
Respiratory 237325 237325 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Liposomal Ciprofloxacin Hydrochloride (HCL) for Inhalation is a dispersion developed for inhalation consisting of ciprofloxacin hydrochloride encapsulated in liposomes and formulated to contain 50 mg/ml of ciprofloxacin. The mixture formulation also referred to as MIXTURE contains equal volumes of this Liposomal Ciprofloxacin Hydrochloride (HCL) for Inhalation (50 mg/ml) [50%] and the Ciprofloxacin Hydrochloride (HCl)
solution (24 mg/ml) for Inhalation [50%]. Formulations will be administered using an AKITA Jet nebulizer or an AKITA Apixneb.nebulizer

Healthy subjects will receive Liposomal Ciprofloxacin HCL for Inhalation doses in the morning .
The three doses are:
A: Liposomal Ciprofloxacin Hydrochloride (HCl) for Inhalation (LC) plus normal saline using AKITA Jet nebulizer in healthy subjects.

B: Liposomal Ciprofloxacin Hydrochloride (HCl) for Inhalation(LC) plus Ciprofloxacin Hydrochloride (HCl) Solution for Inhalation = MIXTURE by AKITA Jet nebulizer in healthy subjects

C: MIXTURE - Liposomal Ciprofloxacin for Inhalation (LC) plus Ciprofloxacin Hydrochloride (HCl) Solution for Inhalation
(FC, combined = MIXTURE) by the Apixneb nebulizer in healthy subjects.
Doses will be randomly assigned to each subject, to be received in one of six different sequences
The intervention administered as three separate formulation/device combinations. Each of the Liposomal Ciprofloxacin Hydrochloride (HCL) for Inhalation treatments will be separated by at least 5 days or 120 hours for ciprofloxacin to wash out of the body.

Non-Cystic Fibrosis (CF) bronchiectasis patients will be screened and six subjects will be selected under separate inclusion and exclusion criteria from the healthy subjects. The single dose selected from the safety and tolerability results of the healthy subject cross-over dosing will be administered as a single dose to the 6 subjects with non-CF bronchiectasis. The reference dose,Tobramycin solution for inhalation(TOBI 'Registered Trademark'), will also be administered to the subjects with non-Cystic Fibrosis (CF) bronchiectasis. The selected dose will only be administered once. The same pre and post dose assessments for each dosing day will apply to the non-Cystic Fibrosis (CF)bronchiectasis population as the healthy subjects.

There are 3 treatment days separated by at least 5 days or 120 hours for ciprofloxacin to wash out of the body. Subjects will report to the Phase I Unit the afternoon prior to the reference treatment day where they will recieve Reference formulation Tobramycin solution for
inhalation (TOBI 'Registered Trademark') administration by inhalation
Intervention code [1] 236749 0
Treatment: Drugs
Comparator / control treatment
Tobramycin solution for
inhalation(TOBI 'Registered Trademark') was selected as a taste and tolerability comparison because it is an approved and marketed product in CF patients with known safety ,tolerability and bitter taste by inhalation.
Tobramycin solution for
inhalation(TOBI 'Registered Trademark') has also been studied in non-Cystic Fibrosis(CF) bronchiectasis patients (Barker etal) It will be administered as a reference with the PARI LC Sprint nebulizer, as approved for use, to determine the acceptability/tolerability of the different formulations/doses given in this study. A cross-over design is used in the study of healthy subjects to have each subject serve as their own control.
The study staff will prepare the reference dose by loading 5 mls from the 5ml ampoule in to the PARI LC Sprint nebulizer for reference formulation dosing.
Control group
Active

Outcomes
Primary outcome [1] 238145 0
To evaluate the safety and tolerability of two different formulations of Liposomal
Ciprofloxacin Hydrochloride (HCL) for Inhalation in two different nebulizers administered as three separate formulation/device combinations, and the tolerability of an inhaled reference
product, tobramycin solution for inhalation (TOBI 'Registered Trademark'), in healthy adults.
Safety and tolerability measurements will be taken for 24 hours after each dosing event. Blood samples for pharmacokinetic measurements will also be acquired over the same 24 hour time period. Subjects will receive a follow-up call from the study staff on the evening of each discharge from the clinic, and at 3 days following each ciprofloxacin dose to be asked if any
adverse events have occurred. Additionally, all subjects will be called 7 days after their last ciprofloxacin dose to ask if any adverse events have occurred.
Timepoint [1] 238145 0
Safety and tolerability measurements will be taken for 24 hours after each dosing event and be based on these results:
Tolerability
Taste questionnaire results and the presence or absence of cough and/or irritation at +15, +30, and +60 minutes relative to dosing following treatment and reference dosing.
Nebulisation time.
Safety endpoints:
Pulmonary Function Test (PFTs) Forced Vital Capacity (FVC), Peak Expiratory Flow Rate (PEFR), Forced Expiratory Volume in the first second of expiration (FEV1), FEV1/FVC ratio, Forced Expiratory Flow in the mid 50% of forced exhalation (FEF25-75,), vital signs, lab tests, Electrocardiogram (ECG), Adverse Events (AEs), physical examination findings, will generally be evaluated as comparisons in continuous variables (mean change) or categorical variables (contingency tables):
Change from pre-dose baseline at each post-dose evaluation where baseline is the
last test prior to dosing.
Blood samples for pharmacokinetic measurements will also be acquired over the same 24 hour time period.
Venous blood specimens will be collected into 9 ml lithium heparin tubes, on all ciprofloxacin treatment
days, at 30 minutes prior to dosing, immediately post-dosing (IPD), and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, and 22 hours after dosing commences
Primary outcome [2] 238146 0
To evaluate the safety and tolerability of a single dose of the selected Liposomal
Ciprofloxacin Hydrochloride (HCL) for Inhalation formulation/device combination in subjects with non-Cystic Fibrosis (CF) bronchiectasis, compared to the tolerability of an inhaled reference product, tobramycin solution for inhalation (TOBI 'Registered Trademark'), and to compare these results with the data acquired in healthy volunteers.
Timepoint [2] 238146 0
The same pre and post dose assessments for each dosing day will apply to the non-CF bronchiectasis population as the healthy subjects. Subjects will receive a follow-up call from the study staff on the evening of each discharge from the clinic, and at 3 days following their ciprofloxacin dose to be asked if any adverse events have occurred. Subjects will return to the Phase 1 unit 7 days (or up to 10 days) after their ciprofloxacin dose for a brief physical
examination, vital signs and pulmonary function testing, together with safety bloods of hematology, biochemistry and urinalysis and questioning about adverse events.

Pre-existing conditions that worsen during a study are to be reported as adverse events. In this study adverse events will be documented and reported from screening to study completion for all subjects who receive at least one dose of the study drug.
Secondary outcome [1] 242359 0
To evaluate the pharmacokinetics of two different Liposomal Ciprofloxacin HCL for
Inhalation formulations in two different nebulizers administered as three separate
formulation/device combinations, in healthy adults
Timepoint [1] 242359 0
Safety and tolerability measurements will be taken for 24 hours after each dosing event.
Blood samples for pharmacokinetic measurements will also be acquired over the same 24 hour
time period. Venous blood specimens will be collected into 9 ml lithium heparin tubes, on all ciprofloxacin treatment
days, at 30 minutes prior to dosing, immediately post-dosing (IPD), and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, and 22 hours after dosing commences
Secondary outcome [2] 242360 0
To evaluate the pharmacokinetics of a single dose of the selected Liposomal
Ciprofloxacin HCL for Inhalation formulation/device combination in subjects with non-CF bronchiectasis.
Timepoint [2] 242360 0
The same pre and post dose assessments for each dosing day will apply to
the non-CF bronchiectasis population as the healthy subjects. Subjects will receive a follow-up call from the study staff on the evening of each discharge from the clinic, and at 3 days following their ciprofloxacin dose to be asked if any adverse events have occurred. Subjects will return to the Phase 1 unit 7 days (or up to 10 days) after their ciprofloxacin dose for a brief physical examination, vital signs and pulmonary function testing, together with safety bloods of hematology, biochemistry and urinalysis and questioning about adverse events.
Secondary outcome [3] 242361 0
To explore the presence or absence of ciprofloxacin in the sputum of subjects with non-CF bronchiectasis before dosing and at three collection time points after inhalation of the selected dose.
Timepoint [3] 242361 0
Sputum samples for ciprofloxacin content will be collected from each subject with
non-CF bronchiectasis before treatment (-30 min), and + 2 hours, +12 hours, and
+ 22 hours after treatment.

Eligibility
Key inclusion criteria
Healthy subjects must be:
- Between 18 and 55 years of age, inclusive
- Healthy subjects as confirmed by medical history, physical examination, vital sign
measurements, pulmonary function tests, ECG as well as blood and urine clinical
laboratory tests;
- Female subjects of child-bearing potential who are sexually active must be willing to
undergo a pregnancy test and agree to use two forms of contraception (e.g. a hormonal
contraception and barrier method contraception or alternatively, two barrier methods [for females not on a hormonal contraceptive]) from screening, for the duration of the study, and up to 30 days after the last dose of study treatment. To be considered “not to be of child-bearing potential”, female subjects must be at least 2 years postmenopausal or have been irreversibly surgically sterilized (by hysterectomy, oophorectomy or bilateral
tubal ligation);
- Body Mass Index (BMI) between 18.5 and 30, inclusive
- Non-smokers for at least 6 months prior to screening (all types of tobacco including
cigars); if an ex-smoker, smoked less than 20 cigarettes (or equivalent) per day over a 10 year period
- Pulmonary function tests within normal limits at screening (= 80% of predicted);
- Good venous access in both arms to allow collection of numerous blood samples;
- Demonstrated ability to take inhaled medications via nebulizer after appropriate training following admission on Rhesus Theta-Defensin-1 (RTD-1)
- Fluent in the English language (written and spoken)
- Provided written informed consent to participate in the study and are willing to comply with all study procedures

Subjects with non-CF bronchiectasis must be:
- Male and female subjects age 18 - 80 years, inclusive
- Confirmed diagnosis of non-CF bronchiectasis per High Resolution Computed Tomography (HRCT) within 3 years of screening
- FEV1 at screening at least 40%, and not greater than 90% of predicted values. FEV1
must also be 1 liter or greater in absolute volume measure
- A history of positive Pseudomonas Aeruginosa (P. aeroginosa) in a sputum/deep-throat cough swab culture or
brochoalveolar lavage [BAL]) within 6 months prior to screening
- Clinically stable and
able to enter the study in the opinion of the investigator
- Female subjects of child-bearing potential who are sexually active must be willing to
undergo a pregnancy test and agree to use two forms of contraception (e.g. a
hormonal contraception and barrier method contraception or alternatively, two barrier
methods [for females not on a hormonal contraceptive]) from screening, for the
duration of the study, and up to 30 days after the last dose of study treatment. To be
considered “not of child-bearing potential”, female subjects must be at least 2 years
postmenopausal, or have been irreversibly surgically sterilized (by hysterectomy,
oophorectomy, or bilateral tubal ligation).
- Non-smokers for at least 6 months prior to screening (all types of tobacco including
cigars)
- Good venous access in both arms to allow collection of numerous blood samples;
- Fluent in the English language (written and spoken);
- Provide written informed consent to participate in the study and be willing to comply with all study procedures.
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Healthy subjects must not have any of the following:
- Participation in another clinical trial within 30 days of screening visit or receipt of an
experimental therapy within 30 days prior to dosing

- Donation >450 ml of blood within 8 weeks of first treatment dose

- Recent (1 year) history of drug or alcohol dependence

- Positive screening test for Human immunodeficiency virus (HIV) antibodies, Hepatitis B surface antigen or Hepatitis C
antibody

- Known or suspected local or systemic hypersensitivity to quinolone antibiotics or
tobramycin

- Viral illness within the last 30 days prior to screening

- Evidence of clinically relevant oral, cardiovascular, hematologic,gastrointestinal,
hepatic, renal, endocrine, pulmonary, neurologic, psychiatric or skin disorder

- Pregnant or breast-feeding

- Males who are sexually active and of reproductive potential and whose female
partners are of child-bearing potential (definition as above) who are not prepared to used adequate birth control, defined as a condom plus spermicidal gel or foam from
screening, for the duration of the study, and up to 30 days after the last dose of
study treatment. Surgical sterilization must be documented in the medical file.

- Use of any ciprofloxacin or related drugs prior to the recruitment interview, such that
these drugs will have been ingested in the 4 weeks prior to the first dosing day

- Use of any other prescription medication (except oral contraceptives) during the 7
days prior to study dosing unless approved by both the Principal Investigator and the
sponsor

- Use of any over the counter product, herbal product, diet aid, hormone supplement, etc., within 7 days of study dosing unless approved by both the Principal Investigator and the sponsor

- Greater than normal alcohol consumption (i.e. more than 21 standard drinks per
week for males, or more than 14 standard drinks per week for females)

- Ingestion of any poppy seeds within the 48 hours prior to the screening blood test
(subjects will be advised by phone not to consume any poppy seed in this time
period)

- Ingestion of any poppy seeds within the 48 hours prior to, or any alcohol, xanthines
(i.e. tea, coffee, caffeine or cola drinks or chocolate) or grapefruit-containing foods or
beverages within the 24 hours prior to, or any of the above within the first 24 hours
after dosing

- Positive urine cotinine result at screening or at admission to clinic (details in
Appendix 1)

- Positive breath alcohol result at screening or at admission to clinic (details in
Appendix 1)

- Detection of any drug listed Appendix 1 (point 4a) in the urine drug screen at
recruitment or any drug listed in Appendix 1 (point 4b) in the urine drug screen at
admission, unless there is an explanation acceptable to the medical investigator (e.g.
the subject has stated in advance that they consumed a prescription product which
contained the detected drug) and/or the subject has a negative urine drug screen on
retest by the pathology laboratory

- Failure to conform to the requirements of the protocol

- Vital signs outside the reference range and clinically significant

- Any clinically significant biochemical or hematological abnormality or any clinically
significant abnormality in the urinalysis result

- Any vigorous exercise or strenuous activity within at least 48 hours before admission
Subjects are requested to refrain as much as possible, from taking concomitant medications from recruitment until the conclusion of their participation in the study.

Subjects with non-CF bronchiectasis must not have any of the following:

- Known or suspected local or systemic hypersensitivity to quinolone antibiotics or
tobramycin.

- History of sputum culture or deep-throat cough swab (or BAL) culture yielding
Burkholderia cepacia (B. cepacia), within 2 years prior to screening and/or sputum
culture yielding B. cepacia at the Screening visit

- Hemoptysis exceeding 50 mL of blood from the respiratory tract at any time within 30 days prior to study drug administration

- Pregnant or breast-feeding

- Males who are sexually active and of reproductive potential and whose female
partners are of child-bearing potential (definition as above) who are not prepared to used adequate birth control, defined as a condom plus spermicidal gel or foam from
screening, for the duration of the study, and up to 30 days after the last dose of
study treatment. Surgical sterilization must be documented in the medical file

- Use of any form of ciprofloxacin or other quinolone antibiotic within 14 days of study
drug administration

- Participation in another clinical trial within 30 days of screening visit or receipt of an
experimental therapy within 30 days prior to study dosing

- Initiation of treatment with chronic macrolide therapy, antibiotic therapy, hypertonic saline by inhalation, or inhaled corticosteroids within 14 days prior to study drug administration (subjects may be taking these therapies at the time of enrollment, but they must have initiated treatment more than 14 days prior to study drug administration)

- Subjects having an exacerbation during the screening process as defined as a
requirement of inhaled, oral, or intravenous antibiotics prior to the first study dose will
be excluded

- Use of any over-the-counter product, herbal product, diet aid, hormone supplement, etc., within 7 days prior to dosing unless approved by both the Principal Investigator and the Sponsor

- Subjects having a diagnosis of cystic fibrosis

- Subjects with clinically significant out of range laboratory values as determined by the investigator

- Ingestion of any poppy seeds within the 48 hours prior to the screening blood test
(subjects will be advised by phone not to consume any poppy seed in this time
period)

- Ingestion of any poppy seeds within the 48 hours prior to, or any alcohol, xanthines
(i.e. tea, coffee, caffeine or cola drinks or chocolate) or grapefruit-containing foods or
beverages within the 24 hours prior to, or any of the above within the first 24 hours
after dosing

- Detection of any drug listed Appendix 1 (point 4a) in the urine drug screen at
recruitment or any drug listed in Appendix 1 (point 4b) in the urine drug screen at
admission, unless there is an explanation acceptable to the medical investigator (e.g.
the subject has stated in advance that they consumed a prescription product which
contained the detected drug) and/or the subject has a negative urine drug screen on
retest by the pathology laboratory

- Donation >450 ml of blood within 8 weeks of first treatment dose

- Recent (1 year) history of drug or alcohol dependence

- Positive screening test for HIV antibodies, Hepatitis B surface antigen or Hepatitis C
antibody

- Positive urine cotinine result at screening or at admission to clinic (details in
Appendix 1)

- Positive breath alcohol result at screening or at admission to clinic (details in
Appendix 1)

- Failure to conform to the requirements of the protocol

- Greater than normal alcohol consumption (i.e. more than 21 standard drinks per
week for males, or more than 14 standard drinks per week for females)

- Vital signs outside the reference range and clinically significant

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
16/03/2009
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
15
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)

Funding & Sponsors
Funding source category [1] 237144 0
Commercial sector/Industry
Name [1] 237144 0
Aradigm Corporation
Country [1] 237144 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Aradigm Corporation
Address
3929 Point Eden Way
Hayward, CA 94545
Country
United States of America
Secondary sponsor category [1] 4635 0
Commercial sector/Industry
Name [1] 4635 0
Clinical Network Services (CNS) Pty Ltd
Address [1] 4635 0
Level 3, 88 Jephson Street
Toowong, Brisbane, QLD 4066
Country [1] 4635 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 239237 0
Queensland Institute of Medical Research (QIMR) - Human Research Ethics Committee
Ethics committee address [1] 239237 0
Ethics committee country [1] 239237 0
Australia
Date submitted for ethics approval [1] 239237 0
Approval date [1] 239237 0
20/02/2009
Ethics approval number [1] 239237 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 29737 0
Address 29737 0
Country 29737 0
Phone 29737 0
Fax 29737 0
Email 29737 0
Contact person for public queries
Name 12984 0
Roberta Lusa
Address 12984 0
Clinical Network Services (CNS) Pty Ltd
Level 3, 88 Jephson Street
Toowong, Brisbane QLD 4066
Country 12984 0
Australia
Phone 12984 0
+61 7 3331 3933
Fax 12984 0
+61 7 3870 0520
Email 12984 0
roberta.lusa@clinical.net.au
Contact person for scientific queries
Name 3912 0
Roberta Lusa
Address 3912 0
Clinical Network Services (CNS) Pty Ltd
Level 3, 88 Jephson Street
Toowong, Brisbane QLD 4066
Country 3912 0
Australia
Phone 3912 0
+61 7 3331 3933
Fax 3912 0
+61 7 3870 0520
Email 3912 0
roberta.lusa@clinical.net.au

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