E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pseudomonas aeruginosa infection in cystic fibrosis patients |
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E.1.1.1 | Medical condition in easily understood language |
Bacterial infection in cystic fibrosis patients |
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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 | 14.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10021860 |
E.1.2 | Term | Infection pseudomonas aeruginosa |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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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 safety of TIP over 6 cycles of treatment in terms of the incidence of treatment emergent adverse events (AEs). |
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E.2.2 | Secondary objectives of the trial |
- To evaluate the safety profile of TIP in terms of acute change in FEV1
- To assess the efficacy of TIP over 6 cycles of treatment, as measured by the relative change in FEV1 , FVC and FEF25-75
- To assess the efficacy of TIP over 6 cycles of treatment, as measured by the absolute change in P. aeruginosa CFU in sputum.
- To evaluate the safety of TIP for P. aeruginosa tobramycin MIC as judged by change from baseline to the end of the dosing periods
- To evaluate the safety profile of TIP in terms of clinical laboratory results and, (in a subset of patients) audiology throughout the treatment period.
- To assess time to first and the rate of hospitalization due to serious respiratory-related AEs
- To assess the time to first and the rate of the usage of anti pseudomonal antibiotic (overall, oral, intravenous) over 6 cycles of TIP treatment other than pre-planned prophylactic treatment planned before enrolment. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Provide written informed consent, HIPAA (Health Insurance Portability and Accountability Act) authorization (where applicable), and assent (as appropriate) prior to the performance of any study-related procedure.
2. Confirmed diagnosis of CF by one or more of the following tests for CF (current or historic):
• quantitative pilocarpine iontophoresis sweat chloride test of > 60 mmol/L,
• genotype with two identifiable CF-causing mutations,
• a positive newborn screening for CF,
• an abnormal nasal transepithelial potential difference characteristic of CF
3. Male and female patients ≥ 6 years of age at screening (Visit 1).
4. FEV1 at screening (Visit 1) must be ≥ 25% and ≤75% of normal predicted values for age, sex, and height based on the Knudson equation.
5. P aeruginosa must be present in a sputum/deep cough throat swab culture (or bronchoalveolar lavage [BAL]) within 6 months prior to screening and in the sputum/ deepthroat cough swab culture at screening (Visit 1).
6. Able to comply with all protocol requirements.
7. Clinically stable in the opinion of the investigator. |
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E.4 | Principal exclusion criteria |
1. History of sputum culture or deep cough throat swab (or BAL) culture yielding Burkholderia cenocepacia (B cc) complex within 2 years prior to screening and/or sputum culture yielding B cc. complex at screening (Visit 1).
2. Hemoptysis more than 60 mL at any time within 30 days prior to study drug administration (Visit 2).
3. History of hearing loss or chronic tinnitus deemed clinically significant by the investigator.
4. Serum creatinine 2 mg/dl or more, BUN 40 mg/dl or more, or an abnormal urinalysis defined as 2+ or greater proteinuria at screening (Visit 1).
5. Known local or systemic hypersensitivity to aminoglycosides or inhaled antibiotics.
6. Patients who are regularly receiving more than 1 class of inhaled anti-pseudomonal antibiotic (inhaled anti-pseudomonal antibiotic are not allowed other than the study drug).
7. Any use of inhaled anti-pseudomonal antibiotics within 28 days prior to study drug administration (Visit 2).
8. Use of systemic anti-pseudomonal antibiotics within 28 days prior to study drug administration (Visit 2).
9. Use of loop diuretics within 7 days prior to study drug administration (Visit 2).
10. Administration of any investigational drug within 30 days prior to enrollment (Visit 1) or 5 halflives, whichever is longer.
11. Signs and symptoms of acute pulmonary disease, e.g., pneumonia, pneumothorax.
12. History of malignancy of any organ system, treated or untreated, regardless of whether there is evidence of local recurrence or metastases.
13. Patients with clinically significant laboratory abnormalities (not associated with the study indication) at screening (Visit 1).
14. Patients with other clinically significant conditions (not associated with the study indication) at screening (Visit 1) which might interfere with the assessment of this study.
15. Patients or caregivers with a history of noncompliance to medical regimens and patients or caregivers who are considered potentially unreliable.
16. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/mL) at screening (Visit 1).
17. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they are using two birth control methods. The two methods can be a double barrier method or a barrier method plus a hormonal method.
- Adequate barrier methods of contraception include: diaphragm, condom (by the partner), intrauterine device (copper or hormonal), sponge or spermicide. Hormonal contraceptives include any marketed contraceptive agent that includes an estrogen and/or a progestational agent.
- Women are considered not of child bearing potential if they have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The incidence of treatment emergent adverse event |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
over 6 cycles of treatment period |
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E.5.2 | Secondary end point(s) |
1) Relative change in FEV1 % predicted, FVC % predicted and FEF25-75 % predicted from baseline
2) Relative change in P aeruginosa CFU in sputum from baseline
3) Change in P aeruginosa tobramycin MIC from baseline
4) Rate of and time to the first hospitalization due to serious respiratory-related AE
5) Rate of and time to the first use of anti-pseudomonal antibiotics (overall, oral, intravenous)
6) Acute change in FEV% predicted from pre-dose to post-dose 30 minutes
7) Evaluation of clinical laboratory results and (in a sub-set of patients) audiology |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) (Visit 2) => At Visit 3, Visit 5, Visit 7, Visit 9, Visit 11, Visit 13, Visit 14.
2) (Visit 2) => At Visit 3, Visit 5, Visit 7, Visit 9, Visit 11, Visit 13, Visit 14.
3) (Visit 2) => At Visit 3, Visit 5, Visit 7, Visit 9, Visit 11, Visit 13, Visit 14
4) over 6 cycles of treatment period
5) over 6 cycles of treatment period
6) At Visit 2, Visit 3, Visit 5, Visit 7, Visit 9, Visit 11, Visit 13.
7) Evaluation of clinical laboratory results and (in a sub-set of patients) audiology: over 6 cycles of treatment period
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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 | 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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
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) | No |
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.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 25 |
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 |
Brazil |
Canada |
France |
Germany |
Hungary |
Italy |
Mexico |
Spain |
United States |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |