Chronic Obstructive Pulmonary Disease Clinical Trial
Official title:
Effects of Dual Bronchodilator Treatment (Tiotropium + Olodaterol Respimat) on Cardiopulmonary Interactions in Hyperinflated Patients With COPD
The deleterious consequences of lung hyperinflation seem not to be restricted to the respiratory system in patients with chronic obstructive pulmonary disease (COPD). Cardiac function, in particular, is strongly influenced by changes in lung volumes and intra-thoracic pressures. In this context, strategies to reduce lung hyperinflation and the work of breathing can positively impact upon cardiac output and blood flow redistribution to peripheral muscles in these patients. There is growing evidence that combination of bronchodilators of different classes is an efficacious and safe strategy for further improving airflow obstruction and hyperinflation in patients with more advanced COPD. Therefore, we aim to investigate that, compared with placebo, a novel LABA/LAMA fixed combination (tiotropium 5 mcg plus olodaterol 5 mcg via Respimat® (Inspiolto®) (TIO/OLO) would decrease lung volumes at rest and during exercise, thereby improving: 1) central and peripheral hemodynamics and 2) arterial oxygenation, with positive consequences on skeletal muscle oxygenation and exercise tolerance in hyperinflated patients with moderate to very severe COPD.
Prospective, proof-of-concept, single-dose study will be conducted using a randomized,
double-blind, placebo-controlled, crossover design. Treatment will consist of a single dose
of tiotropium 5mcg and olodaterol 5mcg via Respimat (Inspiolto)(TIO/OLO) or placebo; the
order of treatment will be randomized. Submaximal cardiopulmonary exercise tests will be
performed 1 hour after inhalation of TIO/OLO or placebo. Changes in blood flow index (BFI)
measured by near-infrared spectroscopy (NIRS) during exercise will be the primary study
endpoint.
Written informed consent will be obtained from all participants prior to performing any study
related procedures. Participants will complete: 1) an initial visit to determine eligibility
for the study; 2) a run-in visit conducted after 2 weeks of stabilization on short-acting
bronchodilator therapy to familiarize subjects with the standardized exercise test
(submaximal cardiopulmonary exercise tests) to be used in the subsequent treatment visits;
and 3) two treatment visits, randomized to order, conducted 3-7 days apart.
Visit 1 will include:
1. A thorough medical history;
2. Clinical assessment;
3. Chronic activity-related dyspnea evaluation;
4. Complete pulmonary function testing;
5. A symptom-limited incremental exercise test on a cycle ergometer to determine maximal
exercise capacity (Wmax); and
6. Post-salbutamol pulmonary function testing for assessment of bronchodilator
responsiveness.
Visit 2 will consist of discontinuous submaximal cardiopulmonary exercise testing for
familiarization.
Visits 3 and 4 will consist of pulmonary function tests (spirometry, plethysmography),
followed by administration of TIO/OLO or placebo. One hour after inhalation, subjects will
perform pulmonary function tests (spirometry, plethysmography) followed immediately by the
submaximal cardiopulmonary exercise tests.
Procedures Pulmonary function testing: Routine spirometry, body plethysmography,
single-breath diffusing capacity of the lung for carbon monoxide (DLCO), and maximum
inspiratory/expiratory mouth pressures will be performed according to recommended techniques
using automatic equipment (Vmax 229d with Vs62j body plethysmograph; SensorMedics, Yorba
Linda, CA). Measurements will be expressed as % of predicted normal values.
Cardiopulmonary exercise testing: Exercise tests will be conducted on an
electronically-braked cycle ergometer using a cardiopulmonary exercise testing system
(Vmax229d; SensorMedics) in accordance with clinical exercise testing guidelines. Incremental
exercise testing at Visit 1 will consist of a steady-state resting period, followed by
followed by 1 minute of loadless pedalling, then 10 watt increases in work-rate every minute
to the point of symptom-limitation. Maximal work rate (Wmax) will be defined as the highest
work rate that the subject is able to maintain for at least 30 seconds. Constant work rate
testing will be conducted at all subsequent visits (see below). Measurements will be
collected at rest and during exercise while subjects breathe through a mouthpiece and a
low-resistance flow transducer with nasal passages occluded by a noseclip. Measurements will
include: standard cardiorespiratory, metabolic and breathing pattern parameters collected on
a breath-by-breath basis and compared with predicted normal values based on age and height;
heart rate by 12-lead electrocardiogram; blood pressure by auscultation; dynamic operating
lung volumes derived from IC maneuvers; oxygen saturation (SpO2) by pulse oximetry;
arterialized blood gases from earlobe samples; the intensity of perceived leg discomfort and
exertional dyspnea rated by the modified 10-point Borg scale. Breath-by-breath measurements
will be averaged every 20-seconds throughout exercise. Three main time points will also be
evaluated: rest will be defined as the steady-state period after at least 3 minutes of
breathing on the mouthpiece while seated at rest on the cycle ergometer before exercise
starts (cardiopulmonary parameters will be averaged over the last 20-sec of this period and
resting ICs will be collected while breathing on the same circuit immediately after
completion of the quiet breathing period); isotime will be defined as the longest duration
achieved during all constant load exercise tests, and; end-exercise will be defined as the
last 30-sec of loaded pedaling at the 75%Wmax stage (i.e., Tlim).
Submaximal cardiopulmonary exercise tests: constant work rate testing will consist of a
steady-state resting period, followed by two stages at unloaded exercise for 5 min and 75% of
Wmax to the limit of tolerance (Tlim. min).
Cardiac output and muscle blood flow and deoxygenation: Cardiac output will be assessed
continuously by a calibrated signal-morphology impedance cardiography system (PhysioFlow;
Manatec Biomedical, France). Near-infrared spectroscopy (NIRS; OxyMon MK III, Artinis Medical
Systems, The Netherlands) will be used to evaluate skeletal muscle blood flow and
deoxygenation. The optode will be placed laterally over the mid-third of the right vastus
lateralis. Deoxy-hemoglobin (HHb) has been selected as a proxy for muscle fractional O2
extraction and expressed relative to maximum values elicited by cuff-induced ischemia. The
NIRS system measures indocyanine green (ICG) concentration following a bolus injection of 5
mg of ICG into a forearm vein. ICG injections will be performed during the fourth minute of
each exercise stage (unloaded and 75%of maximal work load).
Symptom evaluation. Dyspnea (respiratory discomfort) will be defined as the "sensation of
breathing discomfort" and leg discomfort as "the sensation of leg discomfort experienced
during pedalling." These sensations will be rated at rest, every minute during exercise and
at end-exercise using the modified 10-point Borg scale. Upon exercise cessation, subjects
will be asked to verbalize their main reason for stopping exercise, i.e., breathing
discomfort, leg discomfort, combination of breathing and leg discomfort or some other reason
to be specified.
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