| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic obstructive pulmonary disease (COPD) |
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| E.1.1.1 | Medical condition in easily understood language |
| COPD (a smoking related disease of the airways resulting in difficulty breathing) |
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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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10010952 |
| E.1.2 | Term | COPD |
| E.1.2 | System Organ Class | 100000004855 |
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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 |
1) To compare the effect of Trimbow and Fostair on FEV1 [(forced expiratory volume in 1 second – changes from pre-dose day 1)].
2) To compare the effect of Trimbow and Fostair on RV [(residual volume) – changes from pre-dose day 1)]. |
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| E.2.2 | Secondary objectives of the trial |
Secondary:
1) To compare the effect of Trimbow and Fostair on peripheral airway resistance (R5-R20) and expiratory flow limitation (ΔX5) - changes from pre-dose day 1.
2) To compare the effect of Trimbow and Fostair on other measures of Impulse Oscillometry (IOS), Body plethysmography and Spirometry (FVC; FEF25-75%; R5; X5; Fres; AX; TLC; FRC; IC; SGaw; Raw) - changes from pre-dose day 1.
3) To evaluate the effect of Trimbow compared to Baseline (Visit 2) on measures of IOS, Body plethysmography and Spirometry (FEV1, FVC; FEF25-75%; R5; X5; RV; Fres; AX; TLC; FRC; IC; SGaw; Raw).
4) To evaluate the effect of Fostair compared to Baseline (Visit 2) on measures of IOS, Body plethysmography and Spirometry (FEV1, FVC; FEF25-75%; R5; X5; RV; Fres; AX; TLC; FRC; IC; SGaw; Raw).
Other:
To assess the safety and tolerability of the study treatment, as frequency of adverse events (AEs) reported.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male and female adults aged 40 to 75 years with written informed consent obtained prior to any study-related procedure.
2. COPD diagnosis: Subjects with a diagnosis of moderate to severe COPD according to the GOLD 2018 COPD recommendations, with symptoms compatible with COPD for at least 1 year prior to screening.
3. Clinically stable COPD in the 6 weeks prior to screening and during the run-in period prior to randomisation.
4. Body mass index (BMI) in the range of 18.0 to 35.0 kg/m2 and with a minimum weight of 50 kg at screening.
5. Current smokers or ex-smokers with a smoking history of at least 10 pack years [pack-years = (number of cigarettes per day x number of years)/20].
6. A post-bronchodilator FEV1 ≥ 30 % and ≤ 80% of the predicted normal value and a post-bronchodilator FEV1/FVC ratio < 0.7 at screening.
7. Evidence of pre-bronchodilator hyperinflation (RV>120% predicted) at screening (V1) and baseline (V2).
8. Subject is willing and, in the opinion of the Investigator, able to change current COPD therapy as required by the protocol.
9. Subject is treated with double or triple therapy for at least 1 month prior to screening visit with either:
a.Inhaled corticosteroids/long-acting β2-agonist, combination treatment (fixed and/or free)
b.Inhaled corticosteroids and long-acting muscarinic antagonist
c.Inhaled corticosteroids/long-acting β2-agonist/long-acting muscarinic antagonist, combination treatment (fixed and/or free)
In addition to the above subjects may be currently taking inhaled short acting β2-agonists and/or inhaled short acting anticholinergics.
10. A cooperative attitude and ability to be trained to correctly use the pMDI inhaler.
11. Compliance with inhaled Beclometasone run-in medication of between 80 to 120% at Visit 2 (baseline visit) and Visit 3 (Treatment Period 1, Day 1). |
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| E.4 | Principal exclusion criteria |
1. Inability to comply with study procedures, required restrictions, study treatment intake or any other reason that the Investigator considers makes the patient unsuitable to participate.
2. COPD exacerbation requiring oral steroids and/or antibiotics, in the 8 weeks prior to screening or prior to randomisation.
3. Use of antibiotics for a respiratory tract infection in the 8 weeks prior to screening or prior to randomisation.
4. Inability to perform technically acceptable impulse oscillometry, whole body plethysmography or spirometry at screening (V1) or baseline (V2.)
5. Pregnant, lactating or breastfeeding women at screening, baseline or prior to randomisation. Positive urine pregnancy test at screening, baseline or prior to randomisation.
6. A history of one or more hospitalisations for COPD in the 12 months prior to screening or prior to randomisation.
7. Requires oxygen therapy, even on an occasional basis.
8. Known respiratory disorders other than COPD which may impact the efficacy or the safety of the study drug according to investigator’s judgement. This can include but is not limited to known alpha-1 antitrypsin deficiency, active tuberculosis, lung cancer and bronchial carcinoma, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension and interstitial lung disease.
9. An abnormal and clinically significant 12-lead ECG which may impact the safety of the patient according to investigator’s judgement. N.B: Subject whose electrocardiogram (ECG) (12 lead) shows QTcF>450 males or QTcF>470 ms for females at screening are not eligible.
10. Medical diagnosis of narrow-angle glaucoma, prostatic hypertrophy or bladder neck obstruction that in the opinion of the investigator would prevent use of anticholinergic agents.
11. History of hypersensitivity to anticholinergics, β2-agonist, corticosteroids or any of the excipients contained in any of the formulations used in the trial which may raise contra-indications or impact the efficacy of the study drug according to the investigator’s judgement.
12. Clinically significant laboratory abnormalities at screening indicating a significant or unstable concomitant disease which may impact the efficacy of the study drug or the safety of the patient, according to investigator’s judgement.
13. Subjects with a history of chronic uncontrolled disease including, but not limited to, endocrine, active hyperthyroidism, neurological, hepatic, gastrointestinal, renal, haematological, urological, immunological, or ophthalmic diseases that the Investigator believes are clinically significant.
14. Uncontrolled cardiovascular disease: arrhythmias, angina, recent or suspected myocardial infarction, congestive heart failure, a history of unstable, or uncontrolled hypertension, or has been diagnosed with hypertension in the 3 months prior to screening or randomisation.
15. History of alcohol abuse and/or substance/drug abuse within 2 years prior to screening visit.
16. Has had major surgery, (requiring general anaesthesia) in the 8 weeks prior to screening or prior to randomisation, or has planned surgery through the end of the study.
17. Previous lung resection or lung reduction surgery.
18. Participation in another clinical trial and received investigational drug within 30 days (or 5 half-lives whichever is longer). N.B.: For biologic products with slow elimination a washout of at least 6 months needs to be met prior to screening visit.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary efficacy variables:
•Forced Expired Volume in 1 second (FEV1), L
•Residual Volume (RV), L
The primary endpoint will be the area under the FEV1 curve in the 12 hours after treatment on day 5 of each treatment period (AUC0-12).
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Objective 1) FEV1 = Spirometry perfromed pre-dose, 30 minutes, 1, 2, 4, 6, 8, 10 and 12 hours post dose on Day 5 (Treatment Period 1 & 2).
Objective 2) Residual Volume = Whole body plethysmography performed pre-dose, 1, 2, 4, 8 and 12 hours post dose on Day 5 (Treatment Period 1 & 2). |
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| E.5.2 | Secondary end point(s) |
Secondary efficacy variables:
•Forced Vital Capacity (FVC), L
•Forced Expiratory Flow between 25-75% of FVC (FEF25-75%), L/s
•Resistance at 5Hz (R5), kPa/L/s
•Peripheral Respiratory Resistance (R5-R20), kPa/L/s
•Reactance at 5Hz (X5), kPa/L/s
•Expiratory Flow Limitation (Delta X5), kPa/L/s
•Resonance Frequency (Fres), Hz
•Reactance Area (AX), kPa/L
•Total Lung Capacity (TLC), L
•Functional Residual Capacity (FRC), L
•Inspiratory Capacity (IC), L
•Specific Airway Conductance (SGaw), L/s/kPa/L
•Airway Resistance (Raw), kPa/L/s
Safety variables:
•Adverse Events (AEs) and Adverse Drug Reactions (ADRs) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Objective 1) R5-R20 & Delta X5 = IOS performed pre-dose, 30 mins, 1, 2, 4, 6, 8, 10 & 12 hrs post dose on Day 5 (both TPs).
Objective 2) FVC, FEF25-75%, R5, X5, Fres, AX, TLC, FRC, IC, SGaw, Raw = IOS, Spirometry & plethysmography performed pre-dose, 30 mins, 1, 2, 4, 6, 8, 10 & 12 hrs post dose on Day 5 (both TPs).
Objectives 3 & 4) FEV1, FVC, FEF25-75%, R5, X5, RV, Fres, AX, TLC, FRC, IC, SGaw, Raw = IOS, Spirometry & plethysmography performed pre-dose on Day 1 and pre-dose, 30 mins, 1, 2, 4, 6, 8, 10 & 12 hrs post dose on Day 5 (both TPs).
Other Objective) AEs & ADRs = throughout the study from signing consent. |
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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 | 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.8.5 | 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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| The end of the trial is defined as the last scheduled follow up telephone call or last visit to the unit, of the last subject in 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 | 3 |
| E.8.9.1 | In the Member State concerned days | 13 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 13 |
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