| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic obstructive pulmonary disease (COPD) |
|
| E.1.1.1 | Medical condition in easily understood language |
| COPD is a chronic condition of the lung which causes people to suffer symptoms such as shortness of breath and coughing. |
|
| 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 | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10010952 |
| E.1.2 | Term | COPD |
| E.1.2 | System Organ Class | 100000004855 |
|
| 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 show the superiority of glycopyrronium (50 μg o.d.) vs. short-acting
bronchodilators (SABA and/or SAMA as monotherapy or in free or FDC) on FEV1 at week 12.
• To show the non-inferiority of glycopyrronium (50 μg o.d.) vs. longacting
bronchodilators (LABA or LAMA monotherapy) on on FEV1 at week 12.
• To show the superiority of indacaterol maleate and glycopyrronium bromide FDC (110/50 μg o.d.) vs. LABA and ICS in free or FDC on FEV1 at week 12.
• To show the superiority of indacaterol maleate and glycopyrronium bromide FDC (110/50 μg o.d.) vs. long-acting bronchodilators (LABA or
LAMA monotherapy) on on FEV1 at week 12.
• To show the superiority of glycopyrronium (50 μg o.d.) vs. short-acting bronchodilators (SABA and/or SAMA as monotherapy or in free or FDC) on Transition Dyspnea Index (TDI) at week 12.
• To show the non-inferiority of glycopyrronium (50 μg o.d.) vs. longacting
bronchodilators (LABA or LAMA monotherapy) on on TDI at week 12. |
|
| E.2.2 | Secondary objectives of the trial |
• To show the non-inferiority of glycopyrronium (50 μg o.d) vs. shortacting bronchodilators (SABA and/or SAMA as monotherapy or in free or FDC) or long-acting bronchodilators (LABA or LAMA monotherapy) on trough FEV1 at week 12.
• To show the non-inferiority of glycopyrronium (50 μg o.d) vs. shortacting
bronchodilators (SABA and/or SAMA as monotherapy or in free or FDC) or long-acting bronchodilators (LABA or LAMA monotherapy) on TDI at week 12.
• To show the superiority of indacaterol maleate and glycopyrronium bromide FDC (110/50 μg o.d) vs. LABA or LAMA monotherapy or LABA and ICS in free or FDC on trough FEV1 at week 12.
• To show the superiority of indacaterol maleate and glycopyrronium bromide FDC (110/50 μg o.d) vs. LABA or LAMA monotherapy or LABA and ICS in free or FDC on TDI total score at week 12.
• To evaluate the effect of glycopyrronium (50 μg o.d.) and indacaterol maleate and glycopyrronium bromide FDC (110/50 μg o.d) vs. baseline therapy |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patients who have signed an Informed Consent Form before any
assessment is performed.
2. Male and female adults aged ≥ 40 years.
3. Patients with moderate COPD according to the GOLD criteria 2013.
4. Current or ex-smokers who have a smoking history of at least 10 pack years. (Ten pack years are defined as 20 cigarettes a day for 10 years, or 10 cigarettes a day for 20 years. An ex-smoker is defined as a subject who has not smoked for ≥ 6 months at Visit 1.)
5. Patients with airflow limitation indicated by a post-bronchodilator FEV1 ≥50% and <80% of the predicted normal value and a post-bronchodilator FEV1/FVC <0.7 at Visit 2. Post-bronchodilator refers to within 10-15 min of inhalation of 400 μg (4x100 μg) of salbutamol.
6. Patients who, at Visit 1, have been for at least 3 months on a stable dose of one of the following COPD baseline treatments:
- Any SABA monotherapy (such as, but not limited to, salbutamol),
- Any SAMA monotherapy (such as, but not limited to, ipratropium),
- Any SABA and SAMA in free or FDC (such as, but not limited to, salbutamol/ipratropium),
- Any LABA monotherapy (such as, but not limited to, formoterol, salmeterol, indacaterol),
- Any LAMA monotherapy (such as, but not limited to, tiotropium, aclidinium) except glycopyrronium bromide (NVA237),
- Any LABA and ICS in free (ICS such as, but not limited to, beclomethasone, fluticasone) or FDC (such as, but not limited to, salmeterol/fluticasone, formoterol/budesonide)
The exact list of therapies (either active ingredients or FDC) will depend on the available therapies on the market in the participating countries.
7. Patients with an mMRC score ≥1 at Visit 1. |
|
| E.4 | Principal exclusion criteria |
1. Patients with conditions contraindicated for treatment with, or having a history of reactions/ hypersensitivity to any of the following inhaled drugs or to drugs of similar chemical classes or any component thereof:
• Anti-cholinergic agents
• Long- and short-acting β2-adrenergic agonists
• Sympathomimetic amines
• Lactose or any of the other excipients of the trial medication.
2. Patients with narrow-angle glaucoma or urinary retention, severe renal impairment (history of estimated glomerular filtration rate below 30 ml/min/1.73 m2 within 12 months prior to visit 1), including those with end-stage renal disease requiring dialysis.
3. Patients with active/ clinical history of asthma. If the Investigator finds clear and compelling evidence that a patient was misdiagnosed with asthma in the past, then the burden of proof is on the Investigator to properly document this previous misdiagnosis. This documentation must include the rationale for this change in diagnosis including reference to the differential diagnosis that supports this decision.
4. Patients with a history of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.
5. Patients who have a post-bronchodilator FEV1 decrease more than
10% compared to pre-bronchodilator FEV1 result at Visit 2.
6. A documented history of >1 COPD exacerbation requiring treatment with systemic corticosteroids or antibiotics and/or hospitalization in the previous 12 months. Patients who have NOT had a COPD exacerbation in the previous 12 months and develop a COPD exacerbation between screening (Visit 1) and baseline (Visit 2) will not be eligible but will be permitted to be re-screened after a minimum of 6 weeks after the resolution of the COPD exacerbation. (Patients suffering an exacerbation between Visit 1 and Visit 2 can only be re-screened in case it is the first one in the previous 12 months). In case this COPD exacerbation has led to an alteration of the patient COPD treatment, before this patient can be re-screened 3 months of stable COPD treatment will be required as described in Inclusion Criterion 6).
7. Patients who, in the judgment of the investigator, have a clinically relevant laboratory abnormality or a clinically significant condition such as (but not limited to):
• Unstable ischemic heart disease, left ventricular failure (NYHA Class III & IV), history of myocardial infarction, arrhythmia (excluding chronic stable atrial fibrillation). Patients with such events not considered clinically significant by the investigator may be considered for inclusion in the study
• Uncontrolled hypo-or hyperthyroidism, hypokalaemia or hyperadrenergic state
• Any condition which might compromise patient safety or compliance, interfere with evaluation, or preclude completion of the study
8. History of resting QTc (Fridericia preferred, but Bazett acceptable) >450 msec (male) or >460 msec (female) within five years before Visit 1.
9. Patients who are treated with glycopyrronium bromide (NVA237) at visit 1 are not allowed to be included into the trial. Patients on non-selective beta-blockers. Those patients may enter the study after non-selective beta-blocker withdrawal during a 7-day washout period.
10. Patients receiving any other prohibited COPD-related medications specified in Table 5-2 Prohibited COPD-related medications must undergo the required wash-out period prior to Visit 2.
11. Patients who are, in the opinion of the investigator known to be unreliable or non- compliant.
12. Patients with a body mass index (BMI) of more than 40 kg/m2.
13. Use of other investigational drugs within 5 half-lives of enrollment or within 30 days, whichever is longer. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• To show the superiority of glycopyrronium (50 μg o.d.) vs. short-acting bronchodilators (SABA and/or SAMA as monotherapy or in free or FDC) on Transition Dyspnea Index (TDI) at week 12.
• To show the non-inferiority of glycopyrronium (50 μg o.d.) vs. longacting
bronchodilators (LABA or LAMA monotherapy) on TDI at week 12.
• To show the superiority of indacaterol maleate and glycopyrronium
bromide FDC (110/50 μg o.d.) vs. LABA and ICS in free or FDC on TDI at week 12.
• To show the superiority of indacaterol maleate and glycopyrronium
bromide FDC (110/50 μg o.d.) vs. long-acting bronchodilators (LABA or LAMA monotherapy) on TDI at week 12. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• To show the non-inferiority of glycopyrronium (50 μg o.d) vs. shortacting
bronchodilators (SABA and/or SAMA as monotherapy or in free or FDC) or long-acting bronchodilators (LABA or LAMA monotherapy) on TDI at week 12.
• To show the superiority of indacaterol maleate and glycopyrronium
bromide FDC (110/50 μg o.d.) vs. LABA or LAMA monotherapy or LABA and ICS in free or FDC on TDI at week 12.
• To evaluate the effect of glycopyrronium (50 μg o.d.) and indacaterol maleate and glycopyrronium bromide FDC (110/50 μg o.d.) vs. baseline therapy on:
o Total score of COPD Assessment Test (CAT) at week 12
o Total score of Clinical COPD Questionnaire (CCQ) at week 12
o Mean number of puffs of rescue medication use and percentage of days without rescue medication use assessed by electronic patient diary (eDiary) over the 12-week treatment period
o Patient-reported symptoms of COPD assessed by eDiary over the 12-week treatment period
Safety and tolerability over the 12-week treatment period. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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 | 8 |
| 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 | 12 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 780 |
| 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 |
| Austria |
| Belgium |
| Czech Republic |
| Denmark |
| Estonia |
| France |
| Germany |
| Greece |
| Hungary |
| Ireland |
| Italy |
| Latvia |
| Lithuania |
| Norway |
| Poland |
| Portugal |
| Romania |
| Russian Federation |
| Slovakia |
| Slovenia |
| Spain |
| Sweden |
| United Kingdom |
|
| 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
|
|
| 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 | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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