E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Cystic Fibrosis |
Cystická fibróza |
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E.1.1.1 | Medical condition in easily understood language |
Cystic Fibrosis |
Cystická fibróza |
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E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10011764 |
E.1.2 | Term | Cystic fibrosis NOS |
E.1.2 | System Organ Class | 100000004850 |
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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 determine whether inhaled mannitol (400 mg b.i.d.) is superior to control (50mg b.i.d) for improving lung function as measured by mean change from baseline FEV1 (mL) over the 26-week treatment period in adult subjects with cystic fibrosis (CF). |
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E.2.2 | Secondary objectives of the trial |
1. To determine whether inhaled mannitol (400 mg b.i.d.) is superior to control for improving lung function as measured by mean change from baseline FVC (mL) over the 26-week treatment period in adult subjects with CF;
2. To determine whether inhaled mannitol (400 mg b.i.d.) is superior to control in increasing the time to first pulmonary exacerbation over the 26-week treatment period in adult subjects with CF;
3. To determine whether in adult subjects with CF, inhaled mannitol (400 mg b.i.d.) is superior to control for reducing the number of days on antibiotics (oral, inhaled or IV) due to pulmonary exacerbation 4. To determine whether in adult subjects with CF, inhaled mannitol (400 mg b.i.d.) is superior to control for decreasing the number of days in hospital due to pulmonary exacerbation; and
5. To determine whether inhaled mannitol (400 mg b.i.d.) decreases the rate of pulmonary exacerbations over the 26-week treatment period compared to control in adult subjects with CF.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
The subject must meet all of the following criteria:
1. Have given written informed consent to participate in this trial in accordance with local regulations;
2. Have a confirmed diagnosis of cystic fibrosis (positive sweat chloride value ≥ 60 mEq/L) and/or genotype with two identifiable mutations consistent with CF, accompanied by one or more clinical features consistent with the CF phenotype);
3. Be aged at least 18 years old;
4. Have FEV1 > 40 % and < 90% predicted (using NHanes III [1]);
5. Be able to perform all the techniques necessary to measure lung function;
6.Be adherent with maintenance therapies (antibiotics and or rhDNase), if used, for at least 80% of the time in the two weeks prior to visit 1 and
7. If rhDNase and/or maintenance antibiotic are being used treatment must have been established at least 1 month prior to screening (Visit 0). The subject should remain on the rhDNase and / or maintenance antibiotics for the duration of the trial. The subject should not commence treatment with rhDNase or maintenance antibiotics during the trial.
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E.4 | Principal exclusion criteria |
The subject must NOT meet any of the following criteria:
1. Be investigators, site personnel directly affiliated with this trial, or their immediate families. Immediate family is defined as a spouse, parent, child or sibling, whether biologically or legally adopted;
2. Be considered “terminally ill” or eligible for lung transplantation;
3. Have had a lung transplant;
4. Be using maintenance nebulized hypertonic saline in the 2 weeks prior to visit 1;
5. Have had a significant episode of hemoptysis (> 60 mL) in the three months prior to Visit 0;
6. Have had a myocardial infarction in the three months prior to Visit 0;
7. Have had a cerebral vascular accident in the three months prior to Visit 0;
8. Have had major ocular surgery in the three months prior to Visit 0;
9. Have had major abdominal, chest or brain surgery in the three months prior to Visit 0;
10. Have a known cerebral, aortic or abdominal aneurysm;
11. Be breast feeding or pregnant, or plan to become pregnant while in the trial;
12. Be using an unreliable form of contraception (female subjects at risk of pregnancy only);
13. Be participating in another investigative drug trial, parallel to, or within 4 weeks of screening (Visit 0);
14. Have a known allergy to mannitol;
15. Be using non-selective oral beta blockers;
16. Have uncontrolled hypertension –i.e. systolic BP > 190 and / or diastolic BP > 100;
17. Have a condition or be in a situation which in the Investigator’s opinion may put the subject at significant risk, may confound results or may interfere significantly with the subject’s participation in the trial;or
18. Have a failed or incomplete mannitol tolerance test (MTT) (as evaluated in Section 8.1.1.1).
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the mean change in FEV1 (mL) from baseline (Visit 1) over the 26-week treatment period (to Visit 4). |
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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) |
• Mean change from baseline FVC (mL) over the 26-week treatment period;
• Time to first pulmonary exacerbation over the 26-week treatment period;
• Rate of pulmonary exacerbations over the 26-week treatment period;
• Number of days in hospital due to pulmonary exacerbation;
• The incidence of pulmonary exacerbations;
• Number of days on antibiotics (oral, inhaled or IV) due to pulmonary exacerbation;
• Ease of expectoration measured using a visual analogue scale; and
• CFQ-R respiratory domain score.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Throughout the 26 week 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) | 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 | Yes |
E.8.2.3.1 | Comparator description |
Control is a subtherapeutic active, identical to the IMP except for amount of drug in each capsule. |
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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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 54 |
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 |
Belgium |
Canada |
Czech Republic |
France |
Hungary |
Israel |
Italy |
Mexico |
Poland |
Romania |
Russian Federation |
Slovakia |
South Africa |
Spain |
Ukraine |
United Kingdom |
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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phone call 1 week after LVLS |
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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 |