Single Dose Ultibro Breezhaler by Sd-DPI Versus Ipratropium/Salbutamol by Nebulizer in COPD

Study Overview
=================
Brief Summary
-----------------
Rationale: Inhaled bronchodilators, beta-2-agonist or anticholinergic or combinations, can be delivered by several types of devices: dry powder (DPI), pressurized metered dose inhalers (pMDI), and wet nebulizers. Wet nebulization is available for short-acting bronchodilators only, is cumbersome, and, importantly, has never been scientifically been proven to be more efficacious than delivery by the other two methods. Yet many patients are happy with wet nebulization and in many clinics this administration method prevails. The investigators believe that combined long-acting bronchodilators, are more efficacious than combined short acting bronchodilators per nebulizers. Objective: To test the hypothesis that: The combination of the two long-acting bronchodilators indacaterol and glycopyrronium by dry powder inhalation confers a superior improvement compared to nebulisation with ipratropium/salbutamol, when administered as single dose in patients with stable state chronic obstructive pulmonary disease (COPD). Study design: Investigator initiated, randomised, active controlled, cross-over double-blind (and therefore double-dummy), study comparing the effects of single dose indacaterol/glycopyrronium 110/50 Breezhaler® versus single dose ipratropium/salbutamol nebulisation in patients with COPD in stable state Study population: Patients visiting the outpatient clinics or from general practitioner (GP) practices with COPD GOLD stage A-D, and (FEV1) post-bronchodilator FEV1/ forced vital capacity (FVC) < 70%; post-br FEV1 < 80%pred. Intervention The investigators will compare the effects of single dose indacaterol/glycopyrronium 110/50 Breezhaler® versus single dose ipratropium/salbutamol nebulisation in patients with COPD in stable state Main study parameters/endpoints: Area under the curve (AUC) from 0 to 6 hours of FEV1 with indacaterol and glycopyrronium, compared to nebulisation with ipratropium/salbutamol Nature and extent of the burden and risks associated with participation, benefit and group relatedness: This study has no specific benefits for the participating patients. The study also has no major risks. Minor risks for participants after a single dosis can be throat irritation, cough, headache and dizziness, sinus tachycardia. The combination of treatments with β2-agonist bronchodilators and anticholinergic bronchodilators have been used in daily practice for many years in many countries and they are often prescribed both in COPD. Both indacaterol/glycopyrronium and ipratropium/salbutamol are approved for COPD treatment in the Netherlands

Official Title
-----------------
The Effectiveness of Single Dose Ultibro Breezhaler (Indacaterol/Glycopyrronium) by Sd-DPI Versus Ipratropium/Salbutamol by Nebulizer in Improving FEV1 and Dyspnea During Stable State of COPD

Conditions
-----------------
COPD

Intervention / Treatment
-----------------
* Drug: indacaterol/glycopyrronium 110/50 Breezhaler®
* Device: Placebo by Breezhaler®
* Drug: ipratropium/salbutamol 0,5 mg, 2,5 mg by nebulisation
* Device: Placebo by nebulisation


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: COPD, post-bronchodilator FEV1/FVC < 70%; post-br FEV1 < 80%pred Active mastery of Dutch Written informed consent At least 40 years old Participants must be able to understand and complete protocol requirements, Instructions, and questionnaires provided in Dutch Exclusion Criteria: Non invasive ventilation Saturation by pulse oxymetry <88% Documented history of asthma Instable cardiac disease within 6 months. Known long corrected QT interval (QTC) syndrome Known estimated Glomerular Filtration Rate (EGFR) ( <30 ml/min *1,73m2 Exacerbations of COPD or change of medication for COPD in the last 6 weeks prior to inclusion Allergic reaction or intolerance for a substance used in one of the products or atropine or atropine derived substances Pregnant or lactating females.

Ages Eligible for Study
-----------------
Minimum Age: 40 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: A<br>Participants start with Ultibro (indacaterol/glycopyrronium 110/50) + placebo nebulization , then after a new washout period of 7 days they will receive ipratropium/salbutamol nebulization and placebo Breezhaler Interventions: indacaterol/glycopyrronium 110/50 Breezhaler® ,Placebo by Breezhaler®, ipratropium/salbutamol 0,5 mg, 2,5 mg by nebulisation, Placebo by nebulisation | Drug: indacaterol/glycopyrronium 110/50 Breezhaler®<br> <br> * Other names: Ultibro;Device: Placebo by Breezhaler®<br> <br> Drug: ipratropium/salbutamol 0,5 mg, 2,5 mg by nebulisation<br> <br> * Other names: Combivent;Device: Placebo by nebulisation<br> <br> |
| Other: B<br>Participants start with ipratropium/salbutamol nebulization and placebo Breezhaler , then after a new washout period of 7 days they will receive Ultibro(indacaterol/glycopyrronium 110/50) + placebo nebulization. Interventions: indacaterol/glycopyrronium 110/50 Breezhaler® ,Placebo by Breezhaler®, ipratropium/salbutamol 0,5 mg, 2,5 mg by nebulisation, Placebo by nebulisation | Drug: indacaterol/glycopyrronium 110/50 Breezhaler®<br> <br> * Other names: Ultibro;Device: Placebo by Breezhaler®<br> <br> Drug: ipratropium/salbutamol 0,5 mg, 2,5 mg by nebulisation<br> <br> * Other names: Combivent;Device: Placebo by nebulisation<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the curve (AUC) of FEV1 | Area under the curve (AUC) from 0 to 6 hours of FEV1 with indacaterol and glycopyrronium, compared to nebulisation with ipratropium/salbutamol. | from 0 to 6 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Borg dyspnea score at 30 min | 1. Change in Borg dyspnea score at 30 min: change in Borg score at other time points | 30 min up to 360 minutes | 
| Proportion of patients reaching the minimal clinically important difference (MCID) at all time points | proportion of patients reaching the MCID at all time points (15, 30, 60, 120 240 and 360 min) (1) | all time points (15, 30, 60, 120 240 and 360 min) | 
| Changes in level of hyperinflation (by IC measurement) |  | all time points (15, 30, 60, 120 240 and 360 min) | 
| Time to FEV1 increase of 100 ml |  | all time points (15, 30, 60, 120 240 and 360 min) | 
| Peak effect of FEV1 | Maximum FEV1 per group, calculated using the best FEV1 per participant | from 0 to 6 hours | 
| Time to peak of FEV1 |  | all time points (15, 30, 60, 120 240 and 360 min) | 
| FEV1 |  | at all time points (15, 30, 60, 120 240 and 360 min) | 
| Proportion of participants reaching a difference of 100 ml of inspiratory capacity (IC) |  | Time Frame: all time points (15, 30, 60, 120 240 and 360 min) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Nebulizer, DPI, COPD, indacaterol, ipratropium, glycopyrronium, salbutamol, Breezhaler, Nebuliser, Hyperinflation, Dyspnea, SABA, short-acting muscarinic antagonists (SAMA), long-acting beta2-agonist (LABA), LAMA, FEV1