| 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 |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 15.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10010952 |
| E.1.2 | Term | COPD |
| 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• To evaluate the lung bioavailability of B17MP (active metabolite of BDP) and formoterol as AUC0-t across two different dose strengths of CHF 1535 NEXThaler DPI (100/6 µg, 200/6 µg) with activated charcoal.
• To evaluate the total systemic exposure to B17MP (active metabolite of BDP) and to Formoterol as AUC0-t across two different dose strengths of CHF 1535 NEXThaler DPI (100/6 µg, 200/6 µg) without activated charcoal. |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the lung bioavailability and systemic exposure of BDP when CHF 1535 NEXThaler DPI (100/6 µg, 200/6 µg) is administered with and without activated charcoal, respectively.
• To evaluate the systemic effects as glucose potassium and cortisol levels in plasma when CHF 1535 NEXThaler DPI (100/6 µg, 200/6 µg) is administered without activated charcoal.
• To evaluate the systemic effects (as heart rate and blood pressure) and the general safety and tolerability profile when CHF 1535 NEXThaler DPI (100/6 µg, 200/6 µg) is administered with and without activated charcoal. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male and female adults (≥18 and ≤ 70 years old).
2. Written informed consent obtained by the patient prior to any study-related procedures.
3. Diagnosis of asthma as defined by the GINA guidelines, update 2011, for at least 6 months before the screening visit.
4. Asthmatic patients already treated with low daily doses of ICS (e.g. Budesonide or equivalent ≤ 400 µg/day) or low dose of ICS/LABA fixed combinations. Equivalence to:
• Fluticasone ≤ 250
• BDP non extrafine ≤ 500
• BDP via aerosol (e.g. Clenil Modulite) ≤ 250
• BDP extrafine (e.g. QVAR) ≤ 250
5. Patients with a pre-bronchodilator forced expiratory volume in one second (FEV1) ≥ 70% of the predicted values.
6. Non or ex-smokers who smoked less than 5 pack-years and stopped smoking for at least 1 year. (Pack/year: number of cigarette smoked per day multiplied by the number of years of smoking/20).
7. Body mass index (BMI) ≥18.5 and ≤ 32 kg/m2
8. Ability to perform training with NEXThaler Placebo.
9. Ability to perform training with In Check Dial® (Clement Clarke International, Essex, UK) set for Diskus® resistance.
10. A cooperative attitude to be compliant with study procedures. |
|
| E.4 | Principal exclusion criteria |
1. Pregnant or lactating women or all women physiologically capable of becoming pregnant UNLESS they meet the following definition of post-menopausal: 12 months of natural (spontaneous) documented amenorrhea or are using one or more of the following acceptable methods of contraception:
a. surgical sterilization (e.g. bilateral tubal ligation, hysterectomy)
b. hormonal contraception (implantable, patch, oral, injection)
c. other forms of effective contraception including placement of an intrauterine device (IUD) or intrauterine system (IUS) or barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal cream/foam/gel/ suppository, where available.
2. Significant seasonal variation in asthma or asthma occurring only during episodic exposure to an allergen or a chemical sensitizer.
3. History of near fatal asthma (e.g. brittle asthma, hospitalization for asthma exacerbation in Intensive Care Unit).
4. Patients with abnormal QTcF at Screening Visit: QTcF > 450 msec for male patients and QTcF > 470 msec for female patients.
5. Diagnosis of COPD as defined by the current GOLD guidelines, updates 2011.
6. Hospitalization due to asthma exacerbation within 4 weeks prior to the screening visit or during the run-in period.
7. Lower respiratory tract infection within 4 weeks prior to the screening visit or during the run-in period.
8. History of cystic fibrosis, bronchiectasis or alpha-1 antitrypsin deficiency.
9. History of drug addiction or excessive use of alcohol (weekly intake in excess of 28 units alcohol; one unit being a glass of beer, wine or a measure of spirits), or excessive consumption of xanthine containing substances (daily intake in excess of 5 cups of coffee, tea, cola, etc) or psychological or other emotional problems likely to invalidate informed consent, or limit the ability of the patient to comply with the protocol requirements.
10. Diagnosis of restrictive lung disease.
11. Patients treated with oral or parenteral corticosteroids in the previous 2 months before the screening visit (3 months for parenteral depot corticosteroids).
12. Intolerance or contra-indication to treatment with beta2-agonists and/or inhaled corticosteroids or allergy to any component of the study treatment (refer also to Appendix V, Flixotide SmPC).
13. Having received an investigational drug within 1 month before the screening visit.
14. Significant medical history of and/or treatments for cardiac, renal, neurological, hepatic, endocrine diseases, or any laboratory abnormality indicative of a significant underlying condition, that may interfere with patient’s safety, compliance, or study evaluations, according to the investigator’s opinion.
15. Any patient with active cancer or a history of cancer with less than 5 years disease free survival time (whether or not there is evidence of local recurrence or metastases). |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Pharmacokinetic:
• B17MP AUC0-t
• Formoterol AUC0-t |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Pharmacokinetic:
CHF 1535 NEXThaler DPI with activated charcoal:
• BDP/B17MP: pre-dose (within 60 min from dosing), 5, 10, 15, 30, 45 min, 1, 2, 3, 4, 8 and 12 hours post-dose at each treatment visit.
• Formoterol: pre-dose (within 60 min from dosing), 5, 10, 15, 30, 45 min, 1, 2, 3, 4, 8 and 12 hours post-dose at each treatment visit.
CHF 1535 NEXThaler DPI without activated charcoal:
• BDP/B17MP: pre-dose (within 60 min from dosing), 5, 10, 15, 30, 45 min, 1, 2, 3, 4, 8 and 12 hours post-dose at each treatment visit.
• Formoterol: pre-dose (within 60 min from dosing), 5, 10, 15, 30, 45 min, 1, 2, 3, 4, 8, 12, 16, 18, 20 and 24 hours post-dose at each treatment visit. |
|
| E.5.2 | Secondary end point(s) |
Pharmacokinetic:
• BDP: AUC0-t, AUC0-12h, AUC0-∞, Cmax, tmax and t½
• B17MP: AUC0-12h, AUC0-∞, Cmax, tmax and t½
• Formoterol: AUC0-12h, AUC0-24h, AUC0-∞, Cmax, tmax and t½
Pharmacodynamic:
CHF 1535 NEXThaler DPI with and without activated charcoal:
• Heart rate: AUC0-12h/12h
• Blood Pressure: Systolic Blood Pressure (SBP) AUC0-12h/12h, Diastolic Blood Pressure (DBP) AUC0-12h/12h
CHF 1535 NEXThaler DPI without activated charcoal:
• Plasma glucose AUC0-4h ,AUC0-12h, Cmax, tmax
• Plasma potassium AUC0-4h ,AUC0-12h, Cmin, tmin
• Plasma cortisol AUC0-24h, Cmin, tmin
Safety:
• Adverse events
• Plasma cortisol
• Plasma glucose
• Plasma potassium
• QTcB and QTcF
• Heart Rate
• SBP and DBP |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Pharmacokinetic:
See Section E.5.1.1.
Pharmacodynamic and Safety:
• Vital signs: 12-lead ECG, SBP and DBP at screening; holter ECG monitoring at each treatment visit to measure heart rate (HR), and QT (QTcF and QTcB) and ECG recordings at pre-dose (within 60 minutes from dosing), 5, 10, 15, 30, 45 min, 1, 2, 3, 4, 8 and 12 hours post-dose; SBP and DBP at each treatment visit at pre-dose (within 60 minutes from dosing), 5, 10, 15, 30, 45 min, 1, 2, 3, 4, 8 and 12 hours post-dose.
• Plasma glucose and plasma potassium: pre-dose (within 60 min from dosing), 5, 10, 15, 30, 45 min, 1, 2, 3, 4, 8 and 12 hours post-dose at each treatment visit.
• Plasma cortisol: pre-dose (within 60 min from dosing), 2, 3, 4, 8, 12, 16, 18, 20, 24 hours post-dosing at each treatment visit. |
|
| 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 | No |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 |
| tolerability, bioavailability |
|
| 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) | 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 6 |
| 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 | 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 | |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
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