E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pseudomonas aeruginosa infection in patients with non-cystic fibrosis bronchiectasis |
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E.1.1.1 | Medical condition in easily understood language |
Non-cystic Fibrosis Bronchiectasis |
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E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10006445 |
E.1.2 | Term | Bronchiectasis |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10070295 |
E.1.2 | Term | Infective exacerbation of bronchiectasis |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
- To evaluate the effect of different doses of TIP administered o.d. and one b.i.d. dose on the change in P. aeruginosa bacterial load in sputum as assessed by the change in colony forming units (CFUs) from baseline to Day 29 of treatment, each compared to placebo.
- To assess the safety and tolerability with different doses of TIP administered o.d. and b.i.d. and different regimens (TIP and TIP/placebo cyclical) during the treatment epoch (112 days) and during the follow-up epoch (56 days) for each as compared to placebo. |
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E.2.2 | Secondary objectives of the trial |
Key secondary objectives (for the full list please refer to the protocol):
- To assess the effect of different doses of TIP administered o.d. and one b.i.d. dose and different regimens (TIP and TIP/placebo cyclical) on the frequency, rate (by patient- months), severity and time to onset of pulmonary exacerbations at the end of the treatment epoch and over the entire study, each compared to placebo.
- To assess the efficacy profile of different doses of TIP administered o.d. and one b.i.d. dose and different regimens (TIP and TIP/placebo cyclical), as measured by the time to first use, proportion of patients requiring anti-pseudomonal antibiotics (overall, oral, parenteral) and the duration of treatment of anti-pseudomonal antibiotics, each compared to placebo.
- To assess the time to first hospitalization, proportion of patients requiring hospitalization and the duration of hospitalization due to serious respiratory-related AEs.
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Optional 'serum PK' sub-study:
To evaluate serum PK in approximately 16 patients on active treatment, at least 20-22 patients from each cohort (at least 60 total patients) will participate in a PK sub-study. All patients will be asked to participate in the sub-study until enrollment is fulfilled for each cohort. Patients in this PK subset (20-22 patients/ cohort) will instead provide one serum specimen per specified interval at Visits 101 and 103: pre-dose, 0-1, 1-2, 3-4 and 5-6 h. |
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E.3 | Principal inclusion criteria |
• Written informed consent must be obtained before any assessment is performed.
• Male and female patients of ≥ 18 years of age at screening (Visit 1).
• Proven diagnosis of non-CF BE as documented by computed tomography or high-resolution computed tomography
• At least 2 or more exacerbations treated with oral antibiotics OR 1 or more exacerbation requiring parenteral antibiotic treatment within 12 months prior
to screening.
• FEV1 ≥ 30% predicted at screening (Visit 1).
• P. aeruginosa, must be documented in a respiratory sample at least 1 time within 12 months and also present in the expectorated sputum culture at Visit 1. |
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E.4 | Principal exclusion criteria |
• Patients with a history of cystic fibrosis.
• Patients with a primary diagnosis of bronchial asthma.
• Patients with a primary diagnosis of COPD associated with at least a 20 pack year smoking history.
• Any significant medical condition that is either recently diagnosed or was not stable during the last 3 months, other than pulmonary exacerbations, and that
in the opinion of the investigator makes participation in the trial against the patients’ best interests.
• Clinically significant (in the opinion of the investigator) hearing loss that interferes with patients' daily activities (such as normal conversations)
or chronic tinnitus. Patients with a past history of clinically significant
hearing loss in the opinion of the investigator may be eligible only if
their hearing threshold at screening audiometry is 25dB or lower at
frequencies 0.5-4 kHz. The use of a hearing device is reflective of a
clinically significant hearing loss; hence patients using hearing aids at
screening are not eligible.
• Patients with active pulmonary tuberculosis.
• Patients currently receiving treatment for nontuberculous mycobacterial (NTM) pulmonary disease.
• Patients who are receiving inhaled antipseudomonal antibiotic within 28 days prior to study drug administration (Visit 101). |
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E.5 End points |
E.5.1 | Primary end point(s) |
P. aeruginosa density in sputum: change in P. aeruginosa bacterial load in sputum as
assessed by the change in log10 colony forming units (CFUs) from baseline. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1) Frequency of pulmonary exacerbations (compared to placebo)
2) Time to first use of antipseudomonal antibiotics (compared to placebo)
3) Serum tobramycin concentration
4) Sputum tobramycin concentration
5) P. aeruginosa density in sputum over the entire study duration: Change in P. aeruginosa bacterial load in sputum from baseline as assessed by the change in
colony forming units (CFUs) of P. aeruginosa.
6) Respiratory Symptom Scale Quality of Life Questionnaire for Bronchiectasis (QOL-B): Change from baseline on the Respiratory Symptom Scale QOL-B. Respiratory Symptoms is 1 out of 8 domains of the QOL-B instrument and is graded on a 4-point Likert scale.
7) Rate of pulmonary Exacerbations (compared to placebo)
8) Severity of pulmonary exacerbations (compared to placebo)
9) Time to onset of pulmonary exacerbations (compared to placebo)
10) Proportion of patients requiring antipseudomonal antibiotics (compared to placebo)
11) Duration of antipseudomonal antibiotic treatment (compared to placebo)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) 112 days of treatment and 56 days of follow-up
2) 112 days of treatment and 56 days of follow-up
3) Day 29
4) Day 85
5) 112 days of treatment and 56 days of follow-up
6) 112 days of treatment and 56 days of follow-up
7) 112 days of treatment and 56 days of follow-up
8) 112 days of treatment and 56 days of follow-up
9) 112 days of treatment and 56 days of follow-up
10) 112 days of treatment and 56 days of follow-up
11) 112 days of treatment and 56 days of follow-up |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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) | 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) | Yes |
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 | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | Yes |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
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) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 9 |
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 | 49 |
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 |
Belgium |
France |
Germany |
Ireland |
Italy |
Netherlands |
Spain |
Switzerland |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
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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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 | 1 |
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 |