Effect of Glycopyrronium on Morning Symptoms and Pulmonary Function in Patients With Moderate to Severe COPD

Study Overview
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Brief Summary
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This study purpose is to further study the profiles of glycopyrronium (NVA237) and tiotropium during the first hours after dosing and their impact on pulmonary function, COPD symptoms and ability to perform daily activities by the patient.

Detailed Description
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Randomized, multicenter, blinded, two-period cross-over design. Each treatment will last 28 days. All patients will receive both treatments in a cross-over design, with a wash-out period of 14-19 days in between. The total duration of the study for each patient is approximately 70 days (from randomization) plus 30 days of safety follow-up.

Official Title
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Multicenter, Randomized, Blinded, Two-period Cross-over Study to Assess the Effect of Glycopyrronium (44 Micrograms QD) Versus Tiotropium (18 Micrograms QD) on Morning Symptoms and Pulmonary Function in Patients With Moderate to Severe COPD

Conditions
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COPD

Intervention / Treatment
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* Drug: Glycopyrronium
* Drug: Tiotropium
* Drug: Placebo to glycopyrronium
* Drug: Placebo to tiotropium


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Male and female adults aged ≥ 40 years. Co-operative outpatients with a clinical diagnosis of moderate to severe COPD confirmed by spirometry according to GOLD criteria 2013 and including all of the following: a) Current or ex-smokers who have a smoking history of at least 10 pack years (e.g.10 pack years = 1 pack /day x 10 years or ½ pack/day x 20 years). An ex-smoker may be defined as a subject who has not smoked for ≥ 6 months at Screening. b) Patients with airflow limitation indicated by a post-bronchodilator FEV1 < 80% and ≥ 40% of the predicted normal value at Visit 2 (Post- bronchodilator refers to within 10-15 min of inhalation of 400 µg (4x100 µg) of salbutamol). c) .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). Patients with a COPD Assessment Test (CAT) score ≥ 10 at Visit 2. Exclusion criteria: Patients who have had a COPD exacerbation requiring systemic glucocorticosteroid treatment or antibiotics and/or hospitalization in the 6 weeks prior to Visit 1. In the event of an exacerbation occurring during the Screening period (Visits 1-2), the patient must be discontinued from the study. The patient may be re-enrolled once the inclusion/exclusion criteria are met. Only one re-enrollment is allowed. Patients who have had a respiratory tract infection within 6 weeks prior to Visit 1. Patients who develop a respiratory tract infection between Visit 1 and Visit 2 must discontinue from the trial, but may be permitted to re-enrol at a later date once the inclusion/exclusion criteria have been met. Only one re-enrollment is allowed. Patients on any long-acting bronchodilator therapy. Those patients may enter the study after bronchodilator withdrawal during a 10-day wash-out period (only rescue salbutamol allowed as bronchodilator therapy during wash-out). Patients on fixed combination of long acting β2-agonists/inhaled corticosteroid (LABA/ICS) therapy before screening must be switched to the equivalent dose of ICS monotherapy and salbutamol as rescue. Patients receiving any other prohibited COPD-related medications specified in Table 5-1 must undergo the required wash-out period prior to Visit 2. Patients who have had a clinical history of asthma. Patients with concomitant pulmonary disease, e.g. pulmonary tuberculosis or clinically significant bronchiectasis. Patients with alpha-1-antitrypsin deficiency. Patients with contraindications for LAMA treatment including medical history of symptomatic prostatic hypertrophy, bladder neck obstruction, narrow-angle glaucoma and severe renal impairment (estimated glomerular filtration rate below 30 ml/min/1.73 m2) documented in the previous 6 months. Patients with a history of unstable cardiovascular disease or arrhythmias including atrial fibrillation/flutter or long QT syndrome or whose resting QTcF (calculated according to Fridericia QT correction formula preferred, but Bazett acceptable) is prolonged (≥ 450 msec for males and ≥ 460 msec for females) at screening (Visit 1) or baseline (Visit 2, baseline 1). Concomitant use of agents known to prolong the QT interval unless it can be permanently discontinued for the duration of study. Patients contraindicated for treatment with, or having a history of reactions/ hypersensitivity to any of the following inhaled drugs, drugs of a similar class or any component thereof: -anticholinergic agents - long and short acting 2 agonists -sympathomimetic amines -excipients of the trial medication (lactose monohydrate and/or magnesium estearate) Patients whose body mass index (BMI) is less than 15 or greater than 40 kg/m2. 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. Other exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sequence A ⇒ B<br>Participants will receive sequence A = glycopyrronium + placebo to tiotropium during 28 days, followed by a 14 day washout period, then sequence B= tiotropium + placebo to glycopyrronium for 28 days. | Drug: Glycopyrronium<br>* Glycopyrronium capsule for inhalation once per day via SDDPI<br>Drug: Tiotropium<br>* Tiotropium capsule for inhalation once per day via HandiHaler® device<br>Drug: Placebo to glycopyrronium<br>* Placebo to glycopyrronium capsule for inhalation once per day via SDDPI<br>Drug: Placebo to tiotropium<br>* Placebo to tiotropium capsule for inhalation once per day via HandiHaler® device<br>|
| Experimental: Sequence B ⇒ A<br>Participants will receive sequence B= tiotropium + placebo to glycopyrronium during 28 days, followed by a 14 day washout period, then sequence A= glycopyrronium + placebo to tiotropium for 28 days. | Drug: Glycopyrronium<br>* Glycopyrronium capsule for inhalation once per day via SDDPI<br>Drug: Tiotropium<br>* Tiotropium capsule for inhalation once per day via HandiHaler® device<br>Drug: Placebo to glycopyrronium<br>* Placebo to glycopyrronium capsule for inhalation once per day via SDDPI<br>Drug: Placebo to tiotropium<br>* Placebo to tiotropium capsule for inhalation once per day via HandiHaler® device<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Forced Expiratory Volume in 1 Second (FEV1) AUC0-4h After First Dose of Treatment. | Forced Expiratory Volume in 1 second (FEV1) Area Under the Curve (AUC) will measured via spirometry and calculated from 0 to 4 hours post-dose on day 1 of study treatment. | Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of Glycopyrronium QD Versus Tiotropium QD on Symptoms Outcome | Comparison of symptoms outcome between glycopyrronium QD versus tiotropium QD will be conducted via the PROMorning COPD Symptoms questionnaire. This questionnaire will be completed by participants at waking-up, pre-inhalation of study treatment (at home), and they will complete Part 2 of PRO-Morning COPD Symptoms questionnaire at site, 3hours post-inhalation of study treatment. The PRO-Morning COPD Symptoms Questionnaire is a self-administered patient reported outcome (PRO) instrument developed by the sponsor to evaluate patients' experience of early morning symptoms of COPD. The questionnaire consists of two parts : predose and postdose. Each part has 6 questions and for each question a scale of 0 to 10 can be reached. For the predose and postdose part of the questionnaire you will have then each a total score of 0-60 by adding the sub-scores for each question, higher scores represent worse severity of COPD morning symptoms | day 1 (baseline) and week 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COPD, early morning symptoms