Clinical trial NCT01536587: Effects of Salmeterol on Autonomic Nervous System
Official title: Effects of Bronchodilatation With Salmeterol on the Autonomic Nervous System
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: 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,
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2012-02-22
Enrollment: 32
Sex: ALL
Minimum age (years): 41
Maximum age (years): 79
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in Muscle Sympathetic Nerve Activity (MSNA) at 2 Hours (Week 0)
timeFrame: Baseline and 2 hours (Week 0)
Secondary outcomes:
measure: Change From Baseline in MSNA (Evaluated by Microneurography as Bursts/100 Heart Beats) at Week 4
timeFrame: Baseline and Week 4
measure: Change From Baseline in MSNA (Evaluated by Microneurography as Bursts/Minute) at 2 Hours (Week 0)
timeFrame: Baseline and 2 hours (Week 0)
measure: Change From Baseline in MSNA (Evaluated by Microneurography as Bursts/Minute) at Week 4
timeFrame: Baseline and Week 4
measure: 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)
timeFrame: Baseline, 2 hours (Week 0), and Week 4
measure: 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)
timeFrame: Baseline, 2 hours (Week 0), and Week 4
measure: 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)
timeFrame: Baseline, 2 hours (Week 0), and Week 4
measure: 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)
timeFrame: Baseline, 2 hours (Week 0), and Week 4
measure: Change From Baseline in Heart Rate Variability (HRV): Absolute Low Frequency (LF) Power at 2 Hours (Week 0) and at Week 4 (ITT Population)
timeFrame: Baseline, 2 hours (Week 0), and Week 4
measure: 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)
timeFrame: Baseline, 2 hours (Week 0), and Week 4
measure: Change From Baseline in Heart Rate Variability (HRV): Absolute High Frequency (HF) Power at 2 Hours (Week 0) and at Week 4 (ITT Population)
timeFrame: Baseline, 2 hours (Week 0), and Week 4
measure: 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)
timeFrame: Baseline, 2 hours (Week 0), and Week 4
measure: Change From Baseline in Heart Rate Variability (HRV): Normalized Low Frequency (LF) Power at 2 Hours (Week 0) and at Week 4 (ITT Population)
timeFrame: Baseline, 2 hours (Week 0), and Week 4
measure: 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)
timeFrame: Baseline, 2 hours (Week 0), and Week 4
measure: Change From Baseline in Heart Rate Variability (HRV): Normalized High Frequency (HF) Power at 2 Hours (Week 0) and at Week 4 (ITT Population)
timeFrame: Baseline, 2 hours (Week 0), and Week 4
measure: 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)
timeFrame: Baseline, 2 hours (Week 0), and Week 4
measure: Change From Baseline in Heart Rate Variability (HRV): Heart Rate at 2 Hours (Week 0) and at Week 4 (ITT Population)
timeFrame: Baseline, 2 hours (Week 0), and Week 4
measure: Change From Baseline in Heart Rate Variability (HRV): Heart Rate at 2 Hours (Week 0) and at Week 4 (ITT-MSNA Population)
timeFrame: Baseline, 2 hours (Week 0), and Week 4
measure: Change From Baseline in Spontaneous Baroreflex Sensitivity (BRS) at 2 Hours (Week 0) and at Week 4 (ITT Population)
timeFrame: Baseline, 2 hours (Week 0), and Week 4
measure: Change From Baseline in Spontaneous Baroreflex Sensitivity (BRS) at 2 Hours (Week 0) and at Week 4 (ITT-MSNA Population)
timeFrame: Baseline, 2 hours (Week 0), and Week 4
measure: Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at 2 Hours (Week 0) and at Week 4 (ITT Population)
timeFrame: Baseline, 2 hours (Week 0), and Week 4
measure: Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at 2 Hours (Week 0) and at Week 4 (ITT-MSNA Population)
timeFrame: Baseline, 2 hours (Week 0), and Week 4
measure: Change From Baseline in Systolic and Diastolic Blood Pressure (BP) at 2 Hours (Week 0) and at Week 4
timeFrame: Baseline, 2 hours (Week 0), and Week 4
measure: Change From Baseline in Respiratory Rate at 2 Hours (Week 0) and at Week 4
timeFrame: Baseline, 2 hours (Week 0), and Week 4
measure: Change From Baseline in Tidal Volume at 2 Hours (Week 0) and at Week 4
timeFrame: Baseline, 2 hours (Week 0), and Week 4
measure: Change From Baseline in Respiratory Minute Volume at 2 Hours (Week 0) and at Week 4
timeFrame: Baseline, 2 hours (Week 0), and Week 4
measure: Change From Baseline in Catecholamines (Plasma Norepinephrine) at 2 Hours (Week 0) and at Week 4
timeFrame: Baseline, 2 hours (Week 0), and Week 4
measure: Change From Baseline in Catecholamines (Plasma Epinephrine) at 2 Hours (Week 0) and at Week 4
timeFrame: Baseline, 2 hours (Week 0), and Week 4
measure: Change From Baseline in Catecholamines (Brain Natriuretic Peptide [BNP]) at 2 Hours (Week 0) and at Week 4
timeFrame: Baseline, 2 hours (Week 0), and Week 4
measure: Change From Baseline in Oxygen Saturation Measured Via Pulse Oxymetry (SpO2) at 2 Hours (Week 0) and at Week 4
timeFrame: Baseline, 2 hours (Week 0), and Week 4
measure: Change From Baseline in Transcutaneous Carbon Dioxide (tCO2) at 2 Hours (Week 0) and at Week 4
timeFrame: Baseline, 2 hours (Week 0), and Week 4
measure: 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
timeFrame: Baseline and Week 4
measure: Number of Participants With Diastolic Dysfunction on Echocardiography at Baseline (Week 0) and at Week 4
timeFrame: Baseline and Week 4
measure: Arterial Stiffness at Baseline (Week 0) and at Week 4
timeFrame: Baseline and Week 4
Other outcomes:
Locations:
city: Goettingen
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Haarmann H, Mohrlang C, Tschiesner U, Rubin DB, Bornemann T, Ruter K, Bonev S, Raupach T, Hasenfuss G, Andreas S. Inhaled beta-agonist does not modify sympathetic activity in patients with COPD. BMC Pulm Med. 2015 Apr 30;15:46. doi: 10.1186/s12890-015-0054-7.