Effects of Long Acting Bronchodilators on CARDiac Autonomic Control in Chronic Obstructive Pulmonary Disease (COPD)

Study Overview
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Brief Summary
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The aim of this interventional, randomized, double-blind, monocentric, cross-over study is to quantify the possible deleterious effect on the cardiac autonomic nervous system control of two long-acting anticholinergic bronchodilatators (tiotropium and glycopyrronium) and one beta-2 agonist long-acting bronchodilatator (indacaterol ) in patients with mild COPD.

Detailed Description
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This is a cross-over study with randomization in terms of 4 treatments: two long-acting muscarinic antagonists (tiotropium and glycopyrronium), one long-acting beta-adrenoceptor agonist(indacaterol) and placebo. Each subject will pass 4 experimental random sessions, separated by at least 48 hours given the pharmacokinetic properties of the drugs tested. During each of the 4 sessions, blood pressure will be measured. Drugs inhaled by the patient will be prepared and administered by the nurse according to the randomization schedule. Patients and investigators will be blinded regarding the administered drug/placebo (anonymized inhaler). After 15 minutes (at rest, at neutral temperature), patients will have continuous measurement of blood pressure and heart rate (by a sphygmomanometer) (1) in supine position and (2) after a passive tilt test on a tilt test table. A flow-volume loop (BDV) will be performed after the tilt table test (measurement of Forced expiratory volume in 1 second (FEV1) and FVC).

Official Title
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Effects of Long Acting Bronchodilators on CARDiac Autonomic Nervous System Control in Patients With COPD

Conditions
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Chronic Obstructive Pulmonary Disease

Intervention / Treatment
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* Drug: Indacaterol
* Drug: Glycopyrronium
* Drug: Tiotropium
* Drug: Placebo
* Procedure: photoplethysmography


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: patients with FEV1 / FVC <70% Exclusion Criteria: beta blocker supraventricular rhythm disorder previous history of respiratory disease other than COPD diabetes autonomic dysfunction dysautonomia renal failure long-term oxygen therapy history of psychiatric illness

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 75 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>The patients receive once a week during 4 weeks, in the order: indacaterol, tiotropium, glycopyrronium and placebo | Drug: Indacaterol<br>* inhalation<br>Drug: Glycopyrronium<br>* inhalation<br>Drug: Tiotropium<br>* inhalation<br>Drug: Placebo<br> <br> Procedure: photoplethysmography<br>* inhalation<br>|
| Experimental: Arm 2<br>The patients receive once a week during 4 weeks, in the order: tiotropium, glycopyrronium, placebo and indacaterol | Drug: Indacaterol<br>* inhalation<br>Drug: Glycopyrronium<br>* inhalation<br>Drug: Tiotropium<br>* inhalation<br>Drug: Placebo<br> <br> Procedure: photoplethysmography<br>* inhalation<br>|
| Experimental: Arm 3<br>The patients receive once a week during 4 weeks, in the order: glycopyrronium, placebo, indacaterol and tiotropium, | Drug: Indacaterol<br>* inhalation<br>Drug: Glycopyrronium<br>* inhalation<br>Drug: Tiotropium<br>* inhalation<br>Drug: Placebo<br> <br> Procedure: photoplethysmography<br>* inhalation<br>|
| Experimental: Arm 4<br>The patients receive once a week during 4 weeks, in the order: placebo, indacaterol and tiotropium and glycopyrronium | Drug: Indacaterol<br>* inhalation<br>Drug: Glycopyrronium<br>* inhalation<br>Drug: Tiotropium<br>* inhalation<br>Drug: Placebo<br> <br> Procedure: photoplethysmography<br>* inhalation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Low-frequency (LF)/High-frequency (HF) ratio in supine position during a tilt table test after bronchodilators inhalation | For each patient, the LF/HF ratio after inhalation of an active drug (indacaterol or glycopyrronium or tiotropium) will be compared to LF / HF ratio measured after inhalation of a placebo. | 10 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Slope of baroreflex in supine position | Drugs vs placebo | 10 minutes | 
| LF / HF ratio derived from the spectral analysis of R-R intervals measured after verticalisation during a tilt table test | Drugs vs placebo | 10 minutes | 
| Total spectral power during a tilt table tes | Drugs vs placebo | 20 minutes | 
| Value of HF (gross value then normalized according to the average R-R interval) during a tilt table tes | Drugs vs placebo | 20 minutes | 
| RMSSD (Root Mean Square of the Successive Differences) index during a tilt table test | Drugs vs placebo | 20 minutes | 
| Variability in blood pressure during a tilt table test | Drugs vs placebo | 20 minutes | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COPD, bronchodilatators, autonomic nervous system, cardiovascular system