| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pseudomonas aeruginosa (PA) infection in patients with cystic fibrosis. |
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| MedDRA Classification |
| 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 quantify any change in % predicted FEV1 compared to baseline on entry to the study at visit 1 (study day 1). The primary efficacy variable will be FEV1 % predicted measured at Visit 6 (week 24). Success will be judged by showing non inferiority in change of FEV1 for patients treated with dry powder inhaled colistimethate sodium compared to nebulised Tobi®.
It is assumed that non-inferiority exists when the lower limit of the 95% confidence interval of the outcome is not more than 3.0% worse than the control group.
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| E.2.2 | Secondary objectives of the trial |
To quantify the comparative changes in microbiological sensitivity of P. aeruginosa in each treatment group as measured by in-vitro MIC.
To compare quality of life on each treatment regime to establish superior ease of administration
To assess the clinical and laboratory safety of 24 weeks treatment with dry powder inhaled colistimethate sodium compared to nebulised Tobi®.
Nutritional status. To compare weight (and BMI) change in each group.
To compare each group for time to first acute respiratory exacerbation and time to first use (and duration of use) of additional anti-pseudomonal intravenous or oral antibiotics administered for the management of acute respiratory exacerbation.
Other pulmonary function tests
Use of concomitant medication including bronchodilators or rescue medication at time of study medication administration.
To assess and compare the drop-out rate in each group using sensitivity analyses.
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
a) Male or female aged 6 years and above.
b) Patients who are receiving Tobi® in a cycle of 28 days active therapy followed by 28 days of rest from treatment.
c) Patients who, on the first day of trial medication administration (Visit 1), will have received a minimum of 2 Tobi® on/off cycles immediately prior to randomisation.
d) If the patient is female and post-menarche/ pre-menopausal and heterosexually active, the patient must be using adequate effective contraceptive methods.
e) Patients 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).
f) Each patient or parent/ guardian must be capable of reading and understanding informed consent (assent for those under the legal contractual age of consent) and the clinical trial information leaflet.
g) Each patient or parent/ guardian must have granted his or her written informed consent (with assent from those under the legal contractual age of consent) before any trial procedure is carried out.
h) Patient must have a documented diagnosis of CF from a specialist CF Unit (genotype and/ or positive sweat tests).
i) 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 at Visit 1. A diagnosis of an acute respiratory exacerbation (which may not necessarily precipitate the need for immediate hospitalisation) is defined as 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.
j) FEV1 must be at least 25% but no more than 75% of predicted value (see Appendix VI for predicted values).
k) Patients with Pseudomonas aeruginosa 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).
l) Patient’s lung function must be clinically stable (investigator’s decision) after completing i.v. therapy (elective or treatment for exacerbation) at Visit 1 prior to randomisation.
m) Patient’s who, on the first day of trial medication administration (Visit 1), will have had at least 28 days but no more than 35 days off TOBI®.
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| E.4 | Principal exclusion criteria |
a) Evidence of an acute respiratory exacerbation on the first day of trial medication administration (Visit 1).
b) Known sensitivity (or previous intolerance) to colistimethate sodium or β2 agonists.
c) Administration of any investigational drug within 28 days prior to first trial medication administration (Visit 1).
d) Patients who have received treatment which has permanently reduced Pseudomonas aeruginosa infection status will not be included (e.g. effective anti-pseudomonal vaccination and gene therapy).
e) Existence of any pre-study medical conditions which, in the judgement of the investigator, warrants exclusion from the study.
f) Patients who are pregnant or breast-feeding, or who plan to become pregnant during the study period.
g) Inability to communicate or co-operate with the investigator due to language problems, poor mental development or impaired cerebral function.
h) Objection by the patient’s usual CF care-giver to their participation in the study.
i) Inability to comply with any of the study procedures or the study regimen (including inability to use study devices i.e. Turbospin® device or PARI LC Plus® nebuliser for duration of the trial).
j) Laboratory parameters falling outside the expected normal ranges for CF (Investigator decision).
k) Children who in the opinion of the investigator would not be reliable in handling the devices.
l) Patients who are or will be receiving an elective course of intravenous antibiotic therapy on the day of anticipated first administration of trial medication (i.e. Visit 1).
m) Patients who, on the first day of trial medication administration (Visit 1), will have had less than 28 days or more than 35 days off Tobi® or less than 28 days off inhaled colistin.
n) Patients who, on the first day of trial medication administration (Visit 1), are receiving anti-pseudomonal agents specifically for the treatment of an exacerbation or pre-scheduled prophylactic courses of oral antibiotics. [Long term use of antibiotics (e.g. ciprofloxacin) for prophylaxis or anti-inflammatories (e.g. azithromycin) is permitted, provided the regimen has been used for at least 28 days and is planned to continue throughout the study.]
o) Patients who need to receive another anti-pseudomonal agent as part of their standard care during the off-cycle of Tobi®. [Long term use of antibiotics (e.g. ciprofloxacin) for prophylaxis or anti-inflammatories (e.g. azithromycin) is permitted, provided the regimen has been used for at least 28 days and is planned to continue throughout the study.]
p) Patients who are infected/ colonised with Burkholderia cepacia.
q) Patients who are complicated by symptoms related to allergic bronchopulmonary aspergillosis (ABPA).
r) Patients who are awaiting heart-lung or lung transplantation, where the transplant is likely to take place within 6 months of the first day of trial medication administration (i.e. Visit 1).
s) Patient’s lung function not clinically stable (investigator’s decision) after completing i.v. therapy (elective or treatment for exacerbation) at Visit 1 prior to randomisation.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
To quantify any change in % predicted FEV1 compared to baseline on entry to the study at visit 1 (study day 1). The primary efficacy variable will be FEV1 % predicted measured at Visit 6 (week 24). Success will be judged by showing non inferiority in change of FEV1 for patients treated with dry powder inhaled colistimethate sodium compared to nebulised Tobi®.
It is assumed that non-inferiority exists when the lower limit of the 95% confidence interval of the outcome is not more than 3.0% worse than the control group.
Assessments for primary and applicable secondary endpoints will be performed at Visit 6 (week 24/exit). As active treatment with Tobi® ceases 4 weeks prior to the end of the study, evaluations of pulmonary function testing and QoL will additionally be performed at Visit 5 (week 20). The primary analysis will be based on the Visit 6 (week 24/exit) assessments, with evaluations from Visit 5 (week 20) providing supportive data. For microbiology resistance testing, any isolate from individual patients recovered at interim and final time points exhibiting greater resistance than the baseline isolate to either colistin or tobramycin from the patient’s initial sample will be tested for cross-resistance at the end of the study to a short panel of antipseudomonal agents.
Patients who develop an acute respiratory exacerbation will continue trial medication throughout the exacerbation and do not need to be withdrawn from the study. |
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| 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 | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| 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) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| 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 | Information not present in EudraCT |
| 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 | Information not present in EudraCT |
| 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 |
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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 | 1 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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