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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.
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).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Arm 1 | Experimental | The patients receive once a week during 4 weeks, in the order: indacaterol, tiotropium, glycopyrronium and placebo |
|
| Arm 2 | Experimental | The patients receive once a week during 4 weeks, in the order: tiotropium, glycopyrronium, placebo and indacaterol |
|
| Arm 3 | Experimental | The patients receive once a week during 4 weeks, in the order: glycopyrronium, placebo, indacaterol and tiotropium, |
|
| Arm 4 | Experimental | The patients receive once a week during 4 weeks, in the order: placebo, indacaterol and tiotropium and glycopyrronium |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Indacaterol | Drug | inhalation |
| |
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Matthieu VEIL-PICARD | CHU Besançon | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Centre Hospitalier Régional Universitaire | Besançon | France |
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| Glycopyrronium |
| Drug |
inhalation |
|
| Tiotropium | Drug | inhalation |
|
| Placebo | Drug |
|
| photoplethysmography | Procedure | inhalation |
|
| 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 |
| ID | Term |
|---|---|
| D029424 | Pulmonary Disease, Chronic Obstructive |
| ID | Term |
|---|---|
| D008173 | Lung Diseases, Obstructive |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| C510790 | indacaterol |
| D006024 | Glycopyrrolate |
| D000069447 | Tiotropium Bromide |
| ID | Term |
|---|---|
| D000644 | Quaternary Ammonium Compounds |
| D000588 | Amines |
| D009930 | Organic Chemicals |
| D009861 | Onium Compounds |
| D011759 | Pyrrolidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D012602 | Scopolamine Derivatives |
| D014326 | Tropanes |
| D053961 | Azabicyclo Compounds |
| D001372 | Aza Compounds |
| D000470 | Alkaloids |
| D019086 | Bridged Bicyclo Compounds, Heterocyclic |
| D006572 | Heterocyclic Compounds, Bridged-Ring |
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