Effects of Dual Bronchodilator Treatment on Cardiopulmonary Interactions in COPD
Condition: Chronic Obstructive Pulmonary Disease
MeSH terms: Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Tiotropium + Olodaterol; PLACEBO
Intervention type(s): Drug; Other
Intervention description(s): tiotropium 5 mcg plus olodaterol 5 mcg via Respimat® single dose; PLACEBO via Respimat® single dose
Other intervention name(s): INSPIOLTO®
Intervention MeSH terms: Tiotropium Bromide; Olodaterol
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Treatment