Effects of Salmeterol on Autonomic Nervous System

GlaxoSmithKline32 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

SINGLE

Enrollment

Conditions

Pulmonary Disease, Chronic Obstructive

Interventions

SalmeterolDRUG

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.

Eligibility

Sex: ALLMin age: 41 YearsMax age: 79 Years

Medical Language ↔ Plain English

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

Locations (1)

GSK Investigational Site

Göttingen, Lower Saxony, Germany

Outcomes

Primary Outcomes

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).

Time frame: Baseline and 2 hours (Week 0)

Secondary Outcomes

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).

Time frame: Baseline and Week 4

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).

Data from ClinicalTrials.gov

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Time frame: Baseline and 2 hours (Week 0)

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).

Time frame: Baseline and Week 4

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).