E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
bronchiectasis: irreversible airway widening OR localized irreversible dilation of part of the bronchial tree |
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E.1.1.2 | Therapeutic area | Body processes [G] - Circulatory and Respiratory Physiological Phenomena [G09] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
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.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objectives of this study are
• To evaluate the efficacy of ciprofloxacin DPI administered BID intermittently for 28 days on study treatment / 28 days off study treatment or 14 days on study treatment / 14 days off study treatment to prolong the time to first exacerbation requiring an intervention with systemic antibiotics in subjects with non CF BE within 48 weeks after start of treatment (as agreed with the US FDA [Food and Drug Administration]).
• To evaluate the efficacy of ciprofloxacin dry powder for inhalation (DPI) administered 2 times a day (BID) intermittently for 28 days on study treatment / 28 days off study treatment or 14 days on study treatment / 14 days off study treatment in reducing the frequency of pulmonary exacerbation requiring an intervention with systemic antibiotics in subjects with non–CF BE (as agreed with the EMA/CHMP and Japan PMDA) within 48 weeks after start of treatment (wording harmonized with amendment no.2). |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are:
• To assess the frequency of pulmonary exacerbations in subjects with non–CF BE. For this secondary exacerbation events are defined as events with systemic antibiotic use and worsening of at least one sign/symptom;
• To assess pathogen eradication and acquisition of new pathogenic organisms not present at baseline;
• To assess the safety and tolerability of different long term regimens of ciprofloxacin DPI;
• To assess the improvement of quality of life by Saint George’s Respiratory Questionnaire;
• To assess the improvement of quality of life by Quality of Life-Bronchiectasis (QOL–B) questionnaire's respiratory symptom domain;
• To assess changes in lung function as measured by changes in forced expiratory volume in 1 second (FEV1).
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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 |
PK substudy integral part of study 15626: Evaluation of concentration of swallowed ciprofloxacin in the gastrointestinal tract after inhalational treatment by determining the drug concentrations in sputum, blood and fecal matter in a subgroup of subjects who provided consent for this sub-study.
PK related objective:
Changes from baseline in inflammatory markers (hsCRP, Polymorphphonuclear leukocytes (PMN) count);
Changes from baseline in sputum inflammatory markers IL-8 and MPO.
Within the report of this study, sputum, feces, and plasma concentrations will be analyzed using descriptive statistical methods in order to provide a first insight into the pharmacokinetics of Ciprofloxacin DPI. In addition the data will be evaluated under a
separate evaluation protocol (13823) using population pharmacokinetic methods to allow pooling with information from other clinical studies in subjects receiving the drug. |
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E.3 | Principal inclusion criteria |
1) Age at least 18 years;
2) Proven and documented diagnosis of non-CF idiopathic or post-infectious BE by CT scan (conventional high resolution CT is considered the standard) including 2 or more lobes and dilated airways compatible with BE at initial diagnosis
3) Positive culture from an adequate sputum sample for Pseudomonas aeruginosa, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, Streptococcus pneumoniae, Stenotrophomonas maltophilia or Burkholderia cepacia obtained at screening and with history ≥2 documented exacerbations in the past 12 months.
4) Stable pulmonary status as indicated by FEV1 (percent of predicted) 30% and <90% (post-bronchodilator, if used as standard of treatment);
5) Stable regimen of standard treatment with:
o Bronchodilators, anticholinergics, inhaled corticosteroids, or mucolytics, if used as chronic treatment for BE, at least for the past 4 weeks prior to screening.
Subjects on maintenance therapy with low-dose systemic corticosteroids should be receiving =< 10 mg/day prednisolone equivalent at least for the past 4 weeks before the screening visit;
and/or
o Macrolides if used as chronic treatment for BE for at least 6 months prior to screening.
6) Sputum production on the majority of days;
7) Ability to follow the inhaler device instructions;
8) Ability to complete questionnaires;
9) Written informed consent;
10) Negative urine pregnancy test result for women of childbearing potential before first dose of study drug;
11) Women of childbearing potential and men must agree to use adequate contraception when sexually active. This applies from the time of signing of the informed consent form (ICF) until 3 months after the last study drug administration. Adequate methods of contraception include vasectomy, or condom use, diaphragm with spermicidal gel, coil (intrauterine device), surgical sterilization, or oral contraceptives. |
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E.4 | Principal exclusion criteria |
1) FEV1 <30% or >=90% predicted (post-bronchodilator);
2) Active allergic bronchopulmonary aspergillosis (ABPA);
3) Active and actively-treated non-tuberculosis mycobacterial (NTM) infection or tuberculosis;
4) Diagnosis of common variable immunodeficiency (CVID);
5) Recent significant hemoptysis (300 mL or requiring blood transfusion) in the preceding 4 weeks before screening (and during the screening period);
6) Primary diagnosis of COPD;
7) Known CF and / or documented chronic bronchial asthma;
8) Administration of any investigational drug within 4 weeks before screening;
9) Medical history of allergies to quinolones or fluoroquinolones;
10) Women who are pregnant, lactating, or in whom pregnancy cannot be excluded;
11) History of tendon disorders related to quinolone treatment;
12) History of myasthenia gravis;
13) Concomitant administration of tizanidine while on study drug;
14) Systemic or inhaled antibiotic treatment for any indication within 4 weeks prior to the administration of study drug; except for chronic macrolide use (see section 6.9).
15) Systemic corticosteroids at >10 mg/day prednisolone equivalent for >14 days within 4 weeks prior to the administration of study drug;
16) If participating in or has participated in other investigational interventional studies within the previous 4 weeks before screening;
17) Subjects with any other conditions (specifically those which are addressed in the warnings and precautions section of the IB) or clinically relevant laboratory findings that the investigator defines as not appropriate for enrollment of a subject into the study 18) Previous assignment to treatment in this study (randomized in Study 15626); subjects who have participated in RESPIRE 1 will not be enrolled in RESPIRE 2. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy variables are the time to first pulmonary exacerbation requiring an intervention with systemic antibiotics within 48 weeks after start of treatment (for the US NDA [New Drug Application]) and the frequency of exacerbations requiring an intervention with systemic antibiotics within 48 weeks for the EU MAA and further ex-US registrations. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
over 48 weeks after baseline |
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E.5.2 | Secondary end point(s) |
• To assess frequency of exacerbations over 48 weeks (US NDA) / time to first exacerbation within 48 weeks after start of treatment (EU MAA);
• To assess frequency of pulmonary exacerbation in subjects with non–CF BE. For this secondary endpoint exacerbation events are defined as events with systemic antibiotic use and worsening of at least one sign/symptom;
• To assess pathogen eradication and acquisition of new pathogenic organisms not present at baseline;
• To assess the safety and tolerability of different long term regimens of ciprofloxacin DPI;
• To assess the improvement of quality of life by Saint George's Respiratory Questionnaire;
• To assess the improvement of quality of life by Quality of Life respiratory symptom domain Questionnaire (QoL-B);
• To assess changes in lung function as measured by changes in forced expiratory volume in 1 second (FEV1). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Confirmatory analyses for pathogen eradication, occurrence of new pathogens and lung function and SGRQ will be evaluated at end of the on-treatment part of the 6th cycle for subjects in the 28 day on/off regimen, at end of the on-treatment part of the 12th cycle for subjects in the 14 day on/off regimen. |
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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 | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
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 | Yes |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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 | 4 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 73 |
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 |
Argentina |
Australia |
Austria |
Brazil |
Bulgaria |
Canada |
China |
Czech Republic |
Germany |
Hong Kong |
Hungary |
Korea, Republic of |
Lithuania |
Netherlands |
New Zealand |
Poland |
Portugal |
Russian Federation |
South Africa |
Taiwan |
Thailand |
Turkey |
United States |
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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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 7 |