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Effects of Salmeterol on Autonomic Nervous System (ESAN)

Primary Purpose

Pulmonary Disease, Chronic Obstructive

Status

Completed

Phase

Phase 4

Locations

Germany

Study Type

Interventional

Intervention

Salmeterol

About this trial

This is an interventional treatment trial for Pulmonary Disease, Chronic Obstructive focused on measuring influence of bronchodilatation with salmeterol on the autonomic nervous systems in COPD patients will be measured using MSNA., Relation of COPD and sympathetic nerve activity is to be evaluated,

Eligibility Criteria

41 Years - 79 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

COPD of GOLD Class II or III with a post-bronchodilator spirometry forced expiratory volume in one second (FEV1) <60% predicted and FEV1/vital capacity (VC) <70% in accordance with the GOLD executive summary
Subject is ambulatory (outpatient)
Subject is therapy-naive (defined as not receiving any previous regular COPD therapy)
Subjects with a current or prior history of ≥10 pack-years of cigarette smoking at Screening Visit. Previous smokers are defined as those who have stopped smoking for at least 1 month prior to Visit 1
Willing to participate in the study, must be able to inhale study medication

Exclusion Criteria:

Women who are pregnant or lactating
Subjects not willing or unable to sign the informed consent before study start
diagnosis of asthma
α-1 antitrypsin deficiency
active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, interstitial lung diseases or other active pulmonary diseases
Subjects with lung volume reduction surgery within the 12 months prior to Screening
Subjects who have been hospitalized due to poorly controlled COPD within 6 weeks prior to the Screening Visit
Subjects with poorly controlled COPD, defined as the occurrence of an exacerbation managed with systemic corticosteroids or antibiotics prescribed by a physician 6 weeks prior to the Screening Visit
Frequent exacerbations necessitating the therapy with inhaled glucocorticosteroids according to the GOLD guideline
COPD with nasal intermittent positive pressure ventilation (NIPPV)
Treatment with drugs having direct sympathomimetic activity (e.g. theophylline, moxonidine, clonidine), Oral medication with beta2-sympathomimetics
Inhaled therapy with anti-cholinergics, sodium cromoglycate or nedocromil sodium
Treatment with systemic, oral or parenteral (intra-articular) corticosteroids
Treatment with strong cytochrome P450 3A4 inhibitors
Treatment with any other investigational drug
Oxygen therapy: Subjects receiving treatment with long-term oxygen therapy (LTOT) or nocturnal oxygen therapy required for greater than 12 hours a day
Subjects who are medically unable to withhold their short-acting beta-agonist (SABA) for the 6-hour period required prior to spirometry testing at each study visit
Subjects with clinically significant sleep apnoea that is uncontrolled
Unstable angina pectoris or signs and history of left heart failure with a left ventricular ejection fraction <40%
Arterial hypertension necessitating treatment with >1 antihypertensive drug
Clinically evident polyneuropathy
Diabetes mellitus necessitating any pharmacological therapy
Severe concomitant disease (likely to reduce life expectancy to less than 3 years)
Other diseases/abnormalities: Subjects with historical or current evidence of clinically significant neurological, psychiatric, renal, hepatic, immunological, endocrine or haematological abnormality that is uncontrolled

Sites / Locations

GSK Investigational Site

Arms of the Study

Arm 1

Arm Type

Other

Arm Label

Single Arm

Arm Description

Inhalation of salmeterol 50 µg twice daily over 4 weeks

Outcomes

Primary Outcome Measures

Change in Muscle Sympathetic Nerve Activity (MSNA) at 2 Hours (Week 0)

Human MSNA is composed of vasoconstrictor impulses grouped in pulse synchronous bursts that usually occur in sequences, preferentially during transient reductions of blood pressure. Sympathetic activity was measured using microneurographic recordings of efferent in the peroneal nerve. MSNA reflects sympathetic discharge to the vascular bed of the skeletal muscle. The change in MSNA (bursts per 100 heart beats [bursts/100 heart beats]) was calculated as the difference in MSNA change from Baseline to after the inhalation of salmeterol (2 hours, Week 0, Visit 1) minus the MSNA change from Baseline to after the inhalation of placebo (1 hour, Week 0, Visit 1).

Secondary Outcome Measures

Change From Baseline in MSNA (Evaluated by Microneurography as Bursts/100 Heart Beats) at Week 4

Human MSNA is composed of vasoconstrictor impulses grouped in pulse synchronous bursts that usually occur in sequences, preferentially during transient reductions of blood pressure. Sympathetic activity was measured using microneurographic recordings of efferent in the peroneal nerve. MSNA reflects sympathetic discharge to the vascular bed of the skeletal muscle. Change in MSNA is expressed in terms of bursts per 100 heart beats (bursts/100 heart beats). Change from Baseline was calculated as the value at Week 4 (Visit 2, after salmeterol inhalation) minus the value at Baseline (Week 0, before any inhalation).

Change From Baseline in MSNA (Evaluated by Microneurography as Bursts/Minute) at 2 Hours (Week 0)

Human MSNA is composed of vasoconstrictor impulses grouped in pulse synchronous bursts that usually occur in sequences, preferentially during transient reductions of blood pressure. Sympathetic activity was measured using microneurographic recordings of efferent in the peroneal nerve. MSNA reflects sympathetic discharge to the vascular bed of the skeletal muscle. The change in MSNA (bursts per minute [bursts/minute]) was calculated as the difference in MSNA change from Baseline to after the inhalation of salmeterol (2 hours, Week 0, Visit 1) minus the MSNA change from Baseline to after the inhalation of placebo (1 hour, Week 0, Visit 1).

Change From Baseline in MSNA (Evaluated by Microneurography as Bursts/Minute) at Week 4

Human MSNA is composed of vasoconstrictor impulses grouped in pulse synchronous bursts that usually occur in sequences, preferentially during transient reductions of blood pressure. Sympathetic activity was measured using microneurographic recordings of efferent in the peroneal nerve. MSNA reflects sympathetic discharge to the vascular bed of the skeletal muscle. Change in MSNA is expressed in terms of bursts per minute (bursts/minute). Change from Baseline was calculated as the value at Week 4 (Visit 2, after salmeterol inhalation) minus the value at Baseline (Week 0, before any inhalation).

Change From Baseline in Heart Rate Variability (HRV): Standard Deviation of NN Intervals (SDNN) at 2 Hours (Week 0) and at Week 4 (ITT Population)

Heart rate variability (HRV) refers to the complex beat-to-beat (NN) variation in heart rate produced by the interplay of sympathetic and parasympathetic neural activity at the sinus node of the heart. SDNN reflects all the cyclic components responsible for variability in the period of recording; therefore, it represents total variability. Change in HRV (SDNN) after salmeterol inhalation is expressed in terms of milliseconds (ms). Change from Baseline was calculated as the value at 2 hours (Week 0 [Visit 1, after salmeterol inhalation]) and the value at Week 4 (Visit 2, after salmeterol inhalation) minus the value at Baseline (Week 0, before any inhalation).

Change From Baseline in Heart Rate Variability (HRV): Standard Deviation of NN Intervals (SDNN) at 2 Hours (Week 0) and at Week 4 (ITT-MSNA Population)

HRV refers to the complex beat-to-beat (NN) variation in heart rate produced by the interplay of sympathetic and parasympathetic neural activity at the sinus node of the heart. SDNN reflects all the cyclic components responsible for variability in the period of recording; therefore, it represents total variability. Change in HRV (SDNN) after salmeterol inhalation is expressed in terms of milliseconds (ms). Change from Baseline was calculated as the value at 2 hours (Week 0 [Visit 1, after salmeterol inhalation]) and the value at Week 4 (Visit 2, after salmeterol inhalation) minus the value at Baseline (Week 0, before any inhalation).

Change From Baseline in Heart Rate Variability (HRV): Square Root of the Mean Squared Difference of Successive NNs (RMSSD) at 2 Hours (Week 0) and at Week 4 (ITT Population)

HRV refers to the complex beat-to-beat (NN) variation in heart rate produced by the interplay of sympathetic and parasympathetic neural activity at the sinus node of the heart. Compared with SDNN, RMSSD is a short-term variation of heart rate. Change in HRV (RMSSD) after salmeterol inhalation is expressed in terms of milliseconds (ms). Change from Baseline was calculated as the value at 2 hours (Week 0 [Visit 1, after salmeterol inhalation]) and the value at Week 4 (Visit 2, after salmeterol inhalation) minus the value at Baseline (Week 0, before any inhalation).

Change From Baseline in Heart Rate Variability (HRV): Square Root of the Mean Squared Difference of Successive NNs (RMSSD) at 2 Hours (Week 0) and at Week 4 (ITT-MSNA Population)

Change From Baseline in Heart Rate Variability (HRV): Absolute Low Frequency (LF) Power at 2 Hours (Week 0) and at Week 4 (ITT Population)

HRV refers to the complex beat-to-beat (NN) variation in heart rate produced by the interplay of sympathetic and parasympathetic neural activity at the sinus node of the heart. HRV frequencies can be analyzed with frequency domain methods: the LF component of the HRV spectrum reflects sympathetic activity. Change in HRV (absolute LF) after salmeterol inhalation is expressed in terms of milliseconds squared (ms^2). Change from Baseline were calculated as the value at 2 hours (Week 0 [Visit 1, after salmeterol inhalation]) and the value at Week 4 (Visit 2, after salmeterol inhalation) minus the value at Baseline (Week 0, before any inhalation).

Change From Baseline in Heart Rate Variability (HRV): Absolute Low Frequency (LF) Power at 2 Hours (Week 0) and at Week 4 (ITT-MSNA Population)

HRV refers to the complex beat-to-beat (N-N) variation in heart rate produced by the interplay of sympathetic and parasympathetic neural activity at the sinus node of the heart. HRV frequencies can be analyzed with frequency domain methods: The LF component of the HRV spectrum reflects sympathetic activity. Change in HRV (absolute LF) after salmeterol inhalation is expressed in terms of milliseconds squared (ms2). Change from Baseline was calculated as the value at 2 hours (Week 0 [Visit 1, after salmeterol inhalation]) and the value at Week 4 (Visit 2, after salmeterol inhalation) minus the value at Baseline (Week 0, before any inhalation), respectively.

Change From Baseline in Heart Rate Variability (HRV): Absolute High Frequency (HF) Power at 2 Hours (Week 0) and at Week 4 (ITT Population)

HRV refers to the complex beat-to-beat (NN) variation in heart rate produced by the interplay of sympathetic and parasympathetic neural activity at the sinus node of the heart. HRV frequencies can be analyzed with frequency domain methods: the HF component of the HRV spectrum reflects parasympathetic activity. Change in HRV (absolute HF) after salmeterol inhalation is expressed in terms of milliseconds squared (ms^2). Change from Baseline was calculated as the value at 2 hours (Week 0 [Visit 1, after salmeterol inhalation]) and the value at Week 4 (Visit 2, after salmeterol inhalation) minus the value at Baseline (Week 0, before any inhalation).

Change From Baseline in Heart Rate Variability (HRV): Absolute High Frequency (HF) Power at 2 Hours (Week 0) and at Week 4 (ITT-MSNA Population)

HRV refers to the complex beat-to-beat (NN) variation in heart rate produced by the interplay of sympathetic and parasympathetic neural activity at the sinus node of the heart. HRV frequencies can be analyzed with frequency domain methods: the HF component of the HRV spectrum reflects parasympathetic activity. Change in HRV (absolute HF) after salmeterol inhalation is expressed in terms of milliseconds squared (ms^2). Change from Baseline was calculated as the value at 2 hours (Week 0 [Visit 1, after salmeterol inhalation]) and the value at Week 4 (Visit 2, after salmeterol inhalation) minus the value at Baseline (Week 0, before any inhalation).

Change From Baseline in Heart Rate Variability (HRV): Normalized Low Frequency (LF) Power at 2 Hours (Week 0) and at Week 4 (ITT Population)

HRV refers to the complex beat-to-beat (NN) variation in heart rate produced by the interplay of sympathetic and parasympathetic neural activity at the sinus node of the heart. HRV frequencies can be analyzed with frequency domain methods: the LF component of the HRV spectrum reflects sympathetic activity. Change in HRV (normalized LF) after salmeterol inhalation is expressed in terms of normalized units that represent the relative value of LF power component in proportion to the total power minus the very LF (VLF) component (LF/(Total Power-VLF)*100). Change from Baseline was calculated as the value at 2 hours (Week 0 [Visit 1, after salmeterol inhalation]) and the value at Week 4 (Visit 2, after salmeterol inhalation) minus the value at Baseline (Week 0, before any inhalation).

Change From Baseline in Heart Rate Variability (HRV): Normalized Low Frequency (LF) Power at 2 Hours (Week 0) and at Week 4 (ITT-MSNA Population)

HRV refers to the complex beat-to-beat (NN) variation in heart rate produced by the interplay of sympathetic and parasympathetic neural activity at the sinus node of the heart. HRV frequencies can be analyzed with frequency domain methods: The LF component of the HRV spectrum reflects sympathetic activity. Change in HRV (normalized LF) after salmeterol inhalation is expressed in terms of normalized units that represent the relative value of LF power component in proportion to the total power minus the very LF (VLF) component (LF/(Total Power-VLF)*100). Change from Baseline was calculated as the value at 2 hours (Week 0 [Visit 1, after salmeterol inhalation]) and the value at Week 4 (Visit 2, after salmeterol inhalation) minus the value at Baseline (Week 0, before any inhalation).

Change From Baseline in Heart Rate Variability (HRV): Normalized High Frequency (HF) Power at 2 Hours (Week 0) and at Week 4 (ITT Population)

HRV refers to the complex beat-to-beat (NN) variation in heart rate produced by the interplay of sympathetic and parasympathetic neural activity at the sinus node of the heart. HRV frequencies can be analyzed with frequency domain methods: the HF component of the HRV spectrum reflects parasympathetic activity. Change in HRV (normalized HF) after salmeterol inhalation is expressed in terms of normalized units that represent the relative value of HF power component in proportion to the total power minus the very LF (VLF) component (HF/(Total Power-VLF)*100). Change from Baseline was calculated as the value at 2 hours (Week 0 [Visit 1, after salmeterol inhalation]) and the value at Week 4 (Visit 2, after salmeterol inhalation) minus the value at Baseline (Week 0, before any inhalation).

Change From Baseline in Heart Rate Variability (HRV): Normalized High Frequency Power (HF) at 2 Hours (Week 0) and at Week 4 (ITT-MSNA Population)

HRV refers to the complex beat-to-beat (NN) variation in heart rate produced by the interplay of sympathetic and parasympathetic neural activity at the sinus node of the heart. HRV frequencies can be analyzed with frequency domain methods: the HF component of the HRV spectrum reflects parasympathetic activity. Change in HRV (normalized HF) after salmeterol inhalation is expressed in terms of normalized units that represent the relative value of HF power component in proportion to the total power minus the very LF (VLF) component (HF/(Total Power-VLF)*100). Change from Baseline was calculated as the value at 2 hours (Week 0 [Visit 1, after salmeterol inhalation]) and the value at Week 4 (Visit 2, after salmeterol inhalation) minus the value at Baseline (Week 0, before any inhalation).

Change From Baseline in Heart Rate Variability (HRV): Heart Rate at 2 Hours (Week 0) and at Week 4 (ITT Population)

Heart rate refers to the speed of the heartbeat, specifically the number of heartbeats per unit of time. Change in HRV (heart rate) after salmeterol inhalation is expressed in terms of the heart rate (beats) per minute (heart rate/min). Change from Baseline was calculated as the value at 2 hours (Week 0 [Visit 1, after salmeterol inhalation]) and the value at Week 4 (Visit 2, after salmeterol inhalation) minus the value at Baseline (Week 0 before any inhalation).

Change From Baseline in Heart Rate Variability (HRV): Heart Rate at 2 Hours (Week 0) and at Week 4 (ITT-MSNA Population)

Change From Baseline in Spontaneous Baroreflex Sensitivity (BRS) at 2 Hours (Week 0) and at Week 4 (ITT Population)

BRS is an important characteristic of baroreflex control and is often noninvasively assessed by relating heart rate (HR) fluctuations to blood pressure (BP) fluctuations. Change in BRS after salmeterol inhalation is expressed in terms of milliseconds per millimeters of mercury (ms/mmHg). Change from Baseline was calculated as the value at 2 hours (Week 0 [Visit 1, after salmeterol inhalation]) and the value at Week 4 (Visit 2, after salmeterol inhalation) minus the value at Baseline (Week 0 before any inhalation).

Change From Baseline in Spontaneous Baroreflex Sensitivity (BRS) at 2 Hours (Week 0) and at Week 4 (ITT-MSNA Population)

Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at 2 Hours (Week 0) and at Week 4 (ITT Population)

Pulmonary function was measured by FEV1, defined as the volume of air that which can be forcibly exhaled from the lungs in the first second of a forced exhalation. Change in FEV1 after salmeterol inhalation is expressed in terms of liters (L). Change from Baseline was calculated as the value at 2 hours (Week 0 [Visit 1, after salmeterol inhalation]) and the value at Week 4 (Visit 2, after salmeterol inhalation) minus the value at Baseline (Week 0, before any inhalation).

Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at 2 Hours (Week 0) and at Week 4 (ITT-MSNA Population)

Change From Baseline in Systolic and Diastolic Blood Pressure (BP) at 2 Hours (Week 0) and at Week 4

Systolic and diastolic BP was manually measured. Change in BP after salmeterol inhalation is expressed in terms of millimeters of mercury (mmHg). Change from Baseline was calculated as the value at 2 hours (Week 0 [Visit 1, after salmeterol inhalation]) and the value at Week 4 (Visit 2, after salmeterol inhalation) minus the value at Baseline (Week 0, before any inhalation).

Change From Baseline in Respiratory Rate at 2 Hours (Week 0) and at Week 4

Respiratory rate is defined as the number of breaths taken within a set amount of time (typically within 60 seconds). Change in respiratory rate after salmeterol inhalation is expressed in terms of respiratory rate (breaths) per minute (min). Change from Baseline was calculated as the value at 2 hours (Week 0 [Visit 1, after salmeterol inhalation]) and the value at Week 4 (Visit 2, after salmeterol inhalation) minus the value at Baseline (Week 0, before any inhalation).

Change From Baseline in Tidal Volume at 2 Hours (Week 0) and at Week 4

Tidal volume is defined as the lung volume representing the normal volume of air displaced between normal inspiration and expiration when extra effort is not applied (normal value is approximately 500 milliliters or 7 milliliters per kilogram of body weight). Change in tidal volume after salmeterol inhalation is expressed in terms of milliliters (mL). Change from Baseline was calculated as the value at 2 hours (Week 0 [Visit 1, after salmeterol inhalation]) and the value at Week 4 (Visit 2, after salmeterol inhalation) minus the value at Baseline (Week 0, before any inhalation).

Change From Baseline in Respiratory Minute Volume at 2 Hours (Week 0) and at Week 4

Respiratory minute volume is defined as the volume of gas inhaled (inhaled minute volume) or exhaled (exhaled minute volume) from a person's lungs per minute. Change in respiratory minute volume after salmeterol inhalation is expressed in terms of milliliters per minute (mL/min). Change from Baseline was calculated as the value at 2 hours (Week 0 [Visit 1, after salmeterol inhalation]) and the value at Week 4 (Visit 2, after salmeterol inhalation) minus the value at Baseline (Week 0, before any inhalation).

Change From Baseline in Catecholamines (Plasma Norepinephrine) at 2 Hours (Week 0) and at Week 4

Catecholamines are important neurotransmitters in the central nervous system and play a crucial role in the autonomic regulation of many homeostatic functions. Change in catecholamines (plasma norepinephrine) after salmeterol inhalation is expressed in terms of nanogramms per liter (ng/L). Change from Baseline was calculated as the value at 2 hours (Week 0 [Visit 1, after salmeterol inhalation]) and the value at Week 4 (Visit 2, after salmeterol inhalation) minus the value at Baseline (Week 0, before any inhalation).

Change From Baseline in Catecholamines (Plasma Epinephrine) at 2 Hours (Week 0) and at Week 4

Catecholamines are important neurotransmitters in the central nervous system and play a crucial role in the autonomic regulation of many homeostatic functions. Change in catecholamines (plasma epinephrine) after salmeterol inhalation is expressed in terms of nanograms per milliliter (ng/mL). Change from Baseline was calculated as the value at 2 hours (Week 0 [Visit 1, after salmeterol inhalation]) and the value at Week 4 (Visit 2, after salmeterol inhalation) minus the value at Baseline (Week 0, before any inhalation).

Change From Baseline in Catecholamines (Brain Natriuretic Peptide [BNP]) at 2 Hours (Week 0) and at Week 4

Catecholamines are important neurotransmitters in the central nervous system and play a crucial role in the autonomic regulation of many homeostatic functions. Change in catecholamines (BNP) after salmeterol inhalation is expressed in terms of picograms per milliliter (pg/mL). Change from Baseline was calculated as the value at 2 hours (Week 0 [Visit 1, after salmeterol inhalation]) and the value at Week 4 (Visit 2, after salmeterol inhalation) minus the value at Baseline (Week 0, before any inhalation).

Change From Baseline in Oxygen Saturation Measured Via Pulse Oxymetry (SpO2) at 2 Hours (Week 0) and at Week 4

Oxygen saturation measures the capacity of blood to transport oxygen to other parts of the body. Oxygen binds to hemoglobin in red blood cells when moving through the lungs. A pulse oximeter uses two frequencies of light (red and infrared) to determine the percentage of hemoglobin in the blood that is saturated with oxygen. The percentage is called blood oxygen saturation, or SpO2. Change in SpO2 after salmeterol inhalation is expressed in terms of percent. Change from Baseline was calculated as the value at 2 hours (Week 0 [Visit 1, after salmeterol inhalation]) and the value at Week 4 (Visit 2, after salmeterol inhalation) minus the value at Baseline (Week 0, before any inhalation).

Change From Baseline in Transcutaneous Carbon Dioxide (tCO2) at 2 Hours (Week 0) and at Week 4

Transcutaneous carbon dioxide monitoring is a noninvasive way of continuously measuring the tension of these gases in the skin. This methodology provides a continuous noninvasive estimation of the arterial CO2 value. Change in tCO2 after salmeterol inhalation is expressed in terms of millimeters of mercury (mmHg). Change from Baseline was calculated as the value at 2 hours (Week 0 [Visit 1, after salmeterol inhalation]) and the value at Week 4 (Visit 2, after salmeterol inhalation) minus the value at Baseline (Week 0, before any inhalation).

Lung Function (Forced Vital Capacity [FVC], Functional Residual Capacity [FRC; Body and Helium], Total Lung Capacity [TLC], and Residual Volume [RV]) at Baseline (Week 0) and at Week 4

FVC is defined as the volume of air that can be forcibly blown out from the lungs after a full inspiration. FRC is defined as the volume of air present in the lungs, specifically the parenchyma tissues, at the end of a passive expiration. TLC is defined as the maximum volume to which the lungs can be expanded with the greatest possible inspiratory effort; it is equal to VC plus the RV and is approximately 5800 milliliters. RV is defined as the amount of gas remaining in the lungs at the end of a maximal exhalation. All parameters describing lung function are expressed in terms of liters (L). Lung function (FVC, FRC [body and helium], TLC, and RV) was evaluated at Baseline (Week 0, [Visit 1, before any inhalation]) and at Week 4 (Visit 2, after salmeterol inhalation).

Number of Participants With Diastolic Dysfunction on Echocardiography at Baseline (Week 0) and at Week 4

Diastolic dysfunction refers to the decline in performance of one (usually the left ventricle) or both (left and right) ventricles during diastole. The number of participants with diastolic dysfunction on echocardiography was evaluated at Baseline (Week 0, [Visit 1, before any inhalation]) and at Week 4 (Visit 2, after salmeterol inhalation).

Arterial Stiffness at Baseline (Week 0) and at Week 4

Arterial stiffness occurs as a consequence of age and arteriosclerosis. Carotid-femoral pulse wave velocity (PWV), a measure of arterial stiffness, is determined from the time taken for the arterial pulse to propagate from the carotid to the femoral artery. PWV was evaluated in terms of meters per second (m/s). PWV after salmeterol inhalation at Baseline (Week 0, [Visit 1, before any inhalation]) and at Week 4 (Visit 2, after inhalation of salmeterol) was assessed.

Full Information

NCT ID

NCT01536587

First Posted

February 2, 2012

Last Updated

March 13, 2014

Sponsor

GlaxoSmithKline

1. Study Identification

Unique Protocol Identification Number

NCT01536587

Brief Title

Effects of Salmeterol on Autonomic Nervous System

Acronym

ESAN

Official Title

Effects of Bronchodilatation With Salmeterol on the Autonomic Nervous System

Study Type

Interventional

2. Study Status

Record Verification Date

March 2014

Overall Recruitment Status

Completed

Study Start Date

July 2012 (undefined)

Primary Completion Date

November 2012 (Actual)

Study Completion Date

November 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

GlaxoSmithKline

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

This is a 4-week non-randomized, partially blinded, single-arm monocentre study in subjects with Chronic Obstructive Pulmonary Disease (COPD) Global Initiative for Chronic Obstructive Lung Disease (GOLD) class II or III with the aim to demonstrate that inhaled therapy with salmeterol reduces sympathetic activity as evaluated by microneurography. A maximum of 32 subjects is planned to be enrolled.

Detailed Description

This is a 4-week non-randomized, partially blinded, single-arm monocentre study in subjects with COPD GOLD class II or III with the aim to demonstrate that inhaled therapy with salmeterol reduces sympathetic activity as evaluated by microneurography. A maximum of 32 subjects is planned to be enrolled. During a complex data registration period comprising the continuous recording of muscle sympathetic nerve activity (MSNA) and respiration and of various other measurements at Visit 1, placebo and 50 μg of salmeterol via Diskus™ inhaler will be administered in a sequential design. Following Visit 1, the subjects will be treated with salmeterol 50 μg twice daily via Diskus inhaler for 4 weeks. At the Final Visit (Visit 2) the data registration period of Visit 1 will be repeated with the only difference that no placebo will be administered. Further endpoints, besides the evaluation of MSNA, include heart rate variability (HRV), spontaneous baroreflex sensitivity and lung function parameters. Study enrolment will be stopped when valid MSNA data on the immediate effect of inhalation (manoeuvres at Visit 1) are available for 24 subjects.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Pulmonary Disease, Chronic Obstructive

Keywords

influence of bronchodilatation with salmeterol on the autonomic nervous systems in COPD patients will be measured using MSNA., Relation of COPD and sympathetic nerve activity is to be evaluated,

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Single Group Assignment

Masking

Participant

Allocation

N/A

Enrollment

32 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Single Arm

Arm Type

Other

Arm Description

Inhalation of salmeterol 50 µg twice daily over 4 weeks

Intervention Type

Drug

Intervention Name(s)

Salmeterol

Intervention Description

At visit 1 the sympathetic activity will be registered using microneurographic recordings of efferent muscle sympathetic nerve activity (MSNA) in the peroneal nerve and respiration over 2 hours, after 20 minutes of recording, 1 dose of placebo will be administered and after a further recording period of 45 minutes a dose of salmeterol 50 µg will be administered which will be followed by a further period of data registration. At visit 2 following 4 weeks of inhaled treatment with salmeterol the same procedures will be performed but a placebo inhalation will not be performed.

Primary Outcome Measure Information:

Title

Change in Muscle Sympathetic Nerve Activity (MSNA) at 2 Hours (Week 0)

Description

Time Frame

Baseline and 2 hours (Week 0)

Secondary Outcome Measure Information:

Title

Change From Baseline in MSNA (Evaluated by Microneurography as Bursts/100 Heart Beats) at Week 4

Description

Human MSNA is composed of vasoconstrictor impulses grouped in pulse synchronous bursts that usually occur in sequences, preferentially during transient reductions of blood pressure. Sympathetic activity was measured using microneurographic recordings of efferent in the peroneal nerve. MSNA reflects sympathetic discharge to the vascular bed of the skeletal muscle. Change in MSNA is expressed in terms of bursts per 100 heart beats (bursts/100 heart beats). Change from Baseline was calculated as the value at Week 4 (Visit 2, after salmeterol inhalation) minus the value at Baseline (Week 0, before any inhalation).

Time Frame

Baseline and Week 4

Title

Change From Baseline in MSNA (Evaluated by Microneurography as Bursts/Minute) at 2 Hours (Week 0)

Description

Human MSNA is composed of vasoconstrictor impulses grouped in pulse synchronous bursts that usually occur in sequences, preferentially during transient reductions of blood pressure. Sympathetic activity was measured using microneurographic recordings of efferent in the peroneal nerve. MSNA reflects sympathetic discharge to the vascular bed of the skeletal muscle. The change in MSNA (bursts per minute [bursts/minute]) was calculated as the difference in MSNA change from Baseline to after the inhalation of salmeterol (2 hours, Week 0, Visit 1) minus the MSNA change from Baseline to after the inhalation of placebo (1 hour, Week 0, Visit 1).

Time Frame

Baseline and 2 hours (Week 0)

Title

Change From Baseline in MSNA (Evaluated by Microneurography as Bursts/Minute) at Week 4

Description

Human MSNA is composed of vasoconstrictor impulses grouped in pulse synchronous bursts that usually occur in sequences, preferentially during transient reductions of blood pressure. Sympathetic activity was measured using microneurographic recordings of efferent in the peroneal nerve. MSNA reflects sympathetic discharge to the vascular bed of the skeletal muscle. Change in MSNA is expressed in terms of bursts per minute (bursts/minute). Change from Baseline was calculated as the value at Week 4 (Visit 2, after salmeterol inhalation) minus the value at Baseline (Week 0, before any inhalation).

Time Frame

Baseline and Week 4

Title

Change From Baseline in Heart Rate Variability (HRV): Standard Deviation of NN Intervals (SDNN) at 2 Hours (Week 0) and at Week 4 (ITT Population)

Description

Time Frame