| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Cystic fibrosis (CF) is an autosomal, recessive inheritable disease caused by a homozygote defect at the long arm of Chromosome 7. This mutation causes absence or defect of the cystic fibrosis transmembrane conductance regulator, an ion channel transporting chloride and bicarbonate ions across the cell membrane in exocrine glands. Decreased chloride transport leads to dehydration of the mucus layer, and decreased bicarbonate to increased mucus adhesion. Mucus stagnation results. |
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| E.1.1.1 | Medical condition in easily understood language |
| Cystic fibrosis is a genetic condition in which the lungs and digestive system become clogged with thick sticky mucus. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| 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 determine the lung deposition of OligoG when administered to cystic fibrosis patients either as a nebulised solution or as a dry powder for inhalation. |
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| E.2.2 | Secondary objectives of the trial |
To determine the radiolabel distribution pattern of the two formulations in the diseased lung, including calculating the ratio of radiolabel in the central airways compared to the peripheral region (C/P index)
To characterise the extra-pulmonary deposition (i.e. oropharyngeal and stomach) of radiolabel including retention in the nebuliser or dry powder inhaler reservoir and deposition on the exhalation filter (if appropriate).
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Aged at least 18 years at screening.
2. Understands and is willing, able and likely to comply with all study procedures and restrictions.
3. Demonstrates understanding of the study and willingness to participate as evidenced by voluntary written informed consent (signed and dated) obtained before any trial-related activities. (Trial-related activities are any procedure that would not have been performed during normal management of the subject.)
4. Male or female with a confirmed diagnosis of cystic fibrosis defined by:
i. Clinical features consistent with the diagnosis of cystic fibrosis (Rosenstein et al., 1998); AND
ii. Sweat chloride ≥ 60 mmol/L by pilocarpine iontophoresis; OR
iii. Genotypic confirmation of 2 CF-causing mutations
5. Positive microbiological finding of Pseudomonas aeruginosa (mucoid or nonmucoid) in expectorated sputum (and/or swab) documented within the last 24 months prior to screening. Negative finding is acceptable provided the proportion of patients with positive findings is at least 80% as possible.
6. At screening, FEV1 must be between 35 and 80% of the predicted normal value following adjustment for age, gender and height according to the Knudson equation (Knudson et al., 1983)
7. Be clinically stable in the opinion of the referring physician at the CF unit.
8. Female subjects of child-bearing potential and male subjects participating in the study who are sexually active must use acceptable contraception. Female subjects documented as being of non-child bearing potential are exempt from the contraceptive requirements. For the purpose of this study, acceptable contraception is defined as:
i. Oral, injected or implanted hormonal methods or contraception; OR
ii. Placement of an intrauterine device (IUD) or intrauterine system (IUS); OR
iii. Barrier methods of contraception: condom or occlusive cap with spermicidal foam/gel/film/cream/suppository
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| E.4 | Principal exclusion criteria |
1. On-going acute illness. Patients must not have needed an outpatient visit, hospitalisation or required any change in therapy for other pulmonary disease between screening and AV1.
2. History of, or planned organ transplantation.
3. Requirement for continuous (24 hour/day) oxygen supplementation.
4. Concomitant administration of inhaled mannitol or hypertonic saline within 48 hours of Period 1, Day 1.
5. Clinically significant abnormal findings on haematology or clinical chemistry. In addition, any value ≥ 3 x the upper limit of normal will exclude the patient from participating in the study.
6. Patients unable to perform pulmonary function tests according to ATS criteria.
7. Pregnant or breast-feeding women. A negative pregnancy test must be demonstrated in females of child-bearing potential at screening.
8. Patients who have participated in any interventional clinical trial within the 28 days prior to AV1.
9. Patients with documented or suspected, clinically significant, alcohol or drug abuse. The determination of clinical significance will be made by the study physician.
10. Known allergies or intolerances to alginates.
11. Any active malignant disease (with the exception of basal cell carcinoma; BCC).
12. Any serious or active medical or psychiatric illness, which in the opinion of the investigator, would interfere with patient treatment, assessment or compliance with the protocol.
13. Haemoptysis more than 60 mL at any time within 30 days before study drug administration.
14. Patients for whom participation in this study will exceed the limits of total radiation exposure allowed in any 12 month period (5 mSv), or will exceed 10 mSv over any three year period.
15. Male patients who are intending to father a child in the 3 months following the study or are unwilling to abstain from sexual intercourse with pregnant or lactating women. Female patients who are intending to become pregnant in the 3 months following the study.
16. Patients who have any non-removable metal objects such as metal plates, screws etc in their head, neck, chest or abdominal area.
17. As a result of a physical examination or screening investigations, the physician responsible considers the patient unfit for the study.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| To qualitatively determine the deposition of radiolabelled OligoG in the lung. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Scintigraphic imaging will be performed at one timepoint only: immediately after dosing. |
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| E.5.2 | Secondary end point(s) |
To determine the radiolabel distribution pattern of the two formulations in the diseased lung, including calculating the ratio of radiolabel in the central airways compared to the peripheral region (C/P index).
To characterise the extra-pulmonary deposition (i.e. oropharyngeal and stomach) of radiolabel including retention in the nebuliser or dry powder inhaler reservoir and deposition on the exhalation filter (if appropriate). |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Scintigraphic imaging will be performed at one timepoint only: immediately after dosing. |
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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 | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Scintigraphic respiratory study |
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| 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 |
| Respiratory investigation study |
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| 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 | 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| 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 | No |
| 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 23 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 23 |
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