| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| patients with cystic fibrosis and chronical infection with Pseudomonas aeruginosa |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10011763 |
| E.1.2 | Term | Cystic fibrosis lung |
|
| 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 serum pharmacokinetics (PK) of inhaled TOBI® (AUC0-90’) of continuous daily dosing regimens with 2x300mg/d Tobramycin Nebulised Solution (=TNS) inhaled with the PARI eFlow® rapid in Cystic Fibrosis (CF) subjects. |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the serum pharmacokinetics (PK) of inhaled TOBI® (AUC0-90’) of continuous daily dosing regimens with 1x300mg/d Tobramycin Nebulised Solution (=TNS) inhaled with the PARI eFlow® rapid in Cystic Fibrosis (CF) subjects.
• To compare the serum PK of inhaled TOBI® (trough-/peak-level) of both dosing regimens in Cystic Fibrosis (CF) Subjects with a FEV1≥80% vs. CF-Subjects with a FEV1<80%.
• To evaluate the change of MIC of P. aeruginosa during a continuous treatment with 1x300mg/d and 2x300mg/d TNS.
• To assess the safety of a continuous daily dosing regimen with 1x300mg/d and 2x300mg/d TNS over 8 weeks, compared to historic safety data of the 4 week on/off dosing regimen with 2x300mg/d.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male and female subjects aged ≥6 years at the time of screening, with an Informed Consent Form signed by patient and if appropriate by parent/legal guardians, prior to any study-related procedure.
2. Confirmed diagnosis of CF by the presence of one or more clinical features of CF in addition to a quantitative pilocarpine iontophoresis sweat chloride test of >60 mEq/L; or identification of well-characterized disease-causing mutations in each CFTR gene; or an abnormal nasal transepithelial potential difference characteristic of CF.
3. P. aeruginosa must be present in sputum or deep throat swab (or bronchoalveolar lavage [BAL]) at the screening visit and within 6 months prior to screening.
|
|
| E.4 | Principal exclusion criteria |
1. History of sputum (or BAL) culture yielding Burkholderia cepacia (B. cepacia) within 2 years prior to screening and/or sputum culture yielding B cepacia at screening.
2. FEV1 <25% of normal predicted values for age, sex, and height based on Knudson criteria at screening [Knudson 1983; criteria programmed into the spirometers].
3. Hemoptysis of more than 60 cc at any time within 30 days prior to study drug administration.
4. Known local or systemic hypersensitivity to aminoglycosides or inhaled antibiotics.
5. GFR<60ml/min/1.73m2 calculated with the Formula by Schwartz [Lhotta 2005, see Appendix 3], BUN 40 mg/dl or more, or an abnormal urinalysis defined as 2+ or greater proteinuria.
6. History of tinnitus or pathologic audiometry that might conceal a worsening of hearing
7. diagnosis of acute or subacute allergic bronchopulmonary aspergillosis (ABPA) as defined by the Consensus Conference on Diagnostic and Screening Criteria for ABPA in CF (Classic case) at screening
8. Initiation of treatment with macrolide antibiotics within 28 days prior to study drug administration (subjects may be taking macrolide antibiotics at the time of enrollment, but they must have initiated treatment at least 28 days prior to study drug administration).
9. Use of loop diuretics within 7 days prior to study drug administration.
10. Initiation of treatment with dornase alpha within 28 days prior to study drug administration (subjects may be taking dornase alpha at the time of enrollment, but they must have initiated treatment at least 28 days prior to study drug administration).
11. Initiation of treatment with inhaled steroids or modification of dose within 28 days prior to study drug administration (subjects may be taking inhaled steroids at the time of enrollment, but they must have initiated treatment at least 28 days prior to study drug administration).
12. Unable to comply with all protocol requirements.
13. Clinically unstable in the opinion of the investigator.
14. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer
15. History of hypersensitivity to the study drug or to drugs with similar chemical structures
16. History of malignancy of any organ system, treated or untreated, within the past 5 years whether or not there is evidence of local recurrence or metastases, with the exception of localized basal cell carcinoma of the skin
17. Women
o who are pregnant or breast feeding (pregnancy 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))
o who are menstruating and capable of becoming pregnant* and not practicing a medically approved method of contraception (Pearl Index <1**) during and up to at least 4 weeks after the end of treatment. A negative pregnancy test (serum) for all women and for girls entering menarche is required with sufficient lead time before inclusion
[*definition of post-menopausal: 12 months of natural (spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels >40 mIU/m or 6 weeks post surgical bilateral oophorectomy with or without hysterectomy
**examples of particularly reliable methods with Pearl Index (PI) <1, according to guidelines of Deutsche Gesellschaft für Gynäkologie und Geburtshilfe:
- Combination pill with estrogen and gestagen (no mini-pill, PI=0.1-0.9)
- Vaginal ring (NuvaRing®, PI=0.65 uncorr.; 0.4 corr.)
- Contraceptive patch (EVRA®, PI= 0.72 uncorr.; 0.9 corr.)
- Estrogen-free ovulation inhibitors (Cerazette®, PI=0.14)
- Progestin-containing contraceptives (Implanon®, PI=0-0.08)
- Injectable 3-month depot progestins (PI=0.3-1.4; 0.88 corr.)
- Intra-uterine progestine device (Mirena®, PI=0.16)]
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary variable is the serum tobramycin AUC0-90’. |
|
| 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 | 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 | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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 | Yes |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| crossover, two dose regimens |
|
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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
|
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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