E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
systemic exposure of colobreathe in cystic fibrosis subjects with chronic pulmonary infection with Pseudomonas aeruginosa |
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E.1.1.1 | Medical condition in easily understood language |
chronic bacterial lung infection in cystic fibrosis patients |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 13.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10011763 |
E.1.2 | Term | Cystic fibrosis lung |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 13.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10011762 |
E.1.2 | Term | Cystic fibrosis |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the magnitude of systemic exposure to colistimethate after repeat dosing with Colobreathe® in adult, adolescent and paediatric subjects with cystic fibrosis. |
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E.2.2 | Secondary objectives of the trial |
• To establish the full PK profile of the drug substance
• To monitor the safety of Colobreathe® after 7 days repeat dosing
• To compare microbiological and LC/MS/MS assays for the detection of colistin/colistimethate
• To estimate treatment compliance
• To assess changes in FEV1 % predicted |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Male or female subjects aged 6-60 years.
• Subjects must have a documented diagnosis of Cystic Fibrosis from a specialist CF Unit (genotype and/ or positive sweat tests).
• If the subject is female and post-menarche/ pre-menopausal and heterosexually active, the patient must be using adequate effective contraceptive methods.
• Subjects will have documented microbiological evidence of “chronic pulmonary infection” with PA infection (including colonisation), defined as either:
(i) ≥ 50% samples (minimum of 3 samples: sputum samples or throat swabs) positive for PA over the previous 12 months prior to the first day of trial medication administration (Visit 1) OR
(ii) two samples (sputum samples or throat swabs) positive for PA over the previous 6 months prior to the first day of trial medication administration (Visit 1).
• Subjects are required to be non-smokers or a past smoker who has not smoked within the past 12 months prior to the first day of trial medication administration (Visit 1).
• Each subject or parent/guardian must be capable of reading and understanding informed consent and the trial information leaflet (or simplified assent document for those under the legal contractual age of consent and able to
read) and understand and must have granted his or her written informed consent (or assent as appropriate) before any trial procedure is carried out.
• Current CF condition must be clinically stable in the investigator’s opinion i.e. there must be no evidence of a current acute respiratory exacerbation within 7 days prior to the first day of trial medication administration (Visit
1).
• Subjects with an FEV1 predicted, greater than 25%. Lung function anticipated in the opinion of the investigator to be clinically stable for the duration of the study.
• Subjects should continue with all pre-existing medications unless specified in the protocol exclusion criteria (4.2). Changes are to be recorded in the CRF with reasons. |
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E.4 | Principal exclusion criteria |
• Evidence of an acute respiratory exacerbation within 7 days prior to the first day of trial medication
administration (Visit 1). The protocol definition of an acute respiratory exacerbation is the presence of at least
four of the following:
(i) Change in appearance of sputum (i.e. increased purulence or volume).
(ii) Increased productive cough, dyspnoea or respiratory rate.
(iii) Progressive physical findings (crackles, rhonchi and air exchange) on chest auscultation.
(iv) New (infiltrates) intrusion on chest X-ray.
(v) Lassitude and decreased exercise tolerance.
(vi) Fever (≥38oC).
(vii) Deterioration of 10% of highest FEV1 score obtained in the last 6 months.
(viii) Decreased appetite.
(ix) Emergence of new pathogen in sputum i.e. a pathogen that causes clinical disease.
If a subject has less than four of the above and receives a course of intravenous antibiotics, or if there is an
unscheduled course without clear evidence of an acute pulmonary infective exacerbation, then this is considered
an acute exacerbation and an exclusion criterion.
• Known allergy/hypersensitivity (or previous intolerance) to colistimethate sodium, or any inhaled dry powder
pharmaceutical.
• Administration of any investigational product within 28 days prior to first trial medication administration (Visit
1).
• Subjects who have received treatment that has permanently reduced PA infection status will not be included
(e.g. effective anti-pseudomonal vaccination and gene therapy).
• Subjects who are or will be receiving a planned/scheduled course of elective iv antibiotic therapy during the
course of the study.
• Subjects who have received iv colistin in previous 28 days.
• Subjects receiving inhaled antibiotics (Colistin, colistimethate, TOBI, aztreonam, ciprofloxacin, levofloxacin or
other aminoglycoside in the previous 72hrs prior to study drug administration. All subjects will be washed out
from inhaled antibiotic medication for 3 days prior to study entry.
• Subjects who are infected with Burkholderia or have active allergic bronchopulmonary aspergillosis (ABPA).
• Existence of any pre-study medical conditions which, in the judgement of the investigator, warrant exclusion
from the study. Pre existing renal impairment is not an exclusion criterion.
• Subjects who are pregnant or breast-feeding, or who plan to become pregnant during the study period.
• Inability to communicate or cooperate with the investigator due to language problems, poor mental development
or impaired cerebral function.
• Inability to comply with any of the study procedures or the study regimen (including inability to use
Colobreathe® inhaler i.e. Turbospin® device for duration of the trial).
• Screening laboratory parameters falling outside the expected normal ranges for CF (investigator decision).
• Evidence of significant hepatic impairment (investigator decision)
• Subjects who in the opinion of the investigator are unsuitable for any reason to participate in the study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the PK profile of the drug substance colistimethate, colistin A and colistin B in plasma, and urine, including plasma Cmax and Tmax in paediatric, adolescent and adult subjects. Also sputum samples will be collated to confirm that drug has been inhaled during administration. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
PK timepoints are predose and post dose (15min, 30min, 1hr, 2hr, 3hr and 6 hrs post dose) for blood samples.
PK timepoints are predose and post dose (0-6 hrs, and 6 hrs post dose) for urine samples.
PK timepoints are predose and 1hr-post-dose for sputum samples |
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E.5.2 | Secondary end point(s) |
• Frequency and severity of AEs
• Clinically significant changes in laboratory values
• Changes in FEV1 % predicted
• Differences between microbiological and LC-MS/MS assay results used to establish systemic exposure of colistin and colistimethate
• Subjects’ compliance on study medication
• “As needed” use of bronchodilators |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Day 1 & day pre-post dose8 assessments |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
|
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 5 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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last visit of the last subject undergoing the trial |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |