The Cardiopulmonary Effect of Inhaled Beta-2-agonists on Adult Patients Born With Ventricular Septum Defects.
Condition: Ventricular Septal Defect
MeSH terms: Heart Septal Defects; Heart Septal Defects, Ventricular
Study type: Interventional
Phase: Phase 4

Summary: 
      The overall objective for this study is to test whether β2-agonists will affect the
      cardiopulmonary capacity of VSD-operated patients compared with un-operated VSD-patients and
      healthy age- and gender-matched controls.
    

Detailed description: 
      1. Background information

           1.1. Investigational product Ventoline® 0,1 mg/dosis inhalation spray.

           The active substance is Salbutamol. Salbutamol is a selective β2-agonist which induces
           relaxation of the bronchial smooth muscles. Common side effects experienced in 1-10% of
           chronic Ventoline® users are tachycardia, cephalgia and tremors. For more information
           about the product go to 12. Appendix 1 - Product summary, which holds the Danish product
           resume from The Danish Health and Medicines Authority.

           1.2 Background Grown-ups with congenital heart disease represent a constantly growing
           cohort (1,2), and with a birth prevalence of 2.62 per 1000 live birth, isolated
           ventricular septal defect (VSD) is the most frequent congenital cardiac malformation
           (3,4). For these patients short- and long-term follow-up studies have displayed low
           complication rates (5-7), and VSD-corrected patients have been assumed to be just as
           healthy and physically fit compared as their peers (8). Nevertheless recent studies have
           demonstrated significant long-term abnormalities (9-12).

           Compared with the normal population similar workloads in ergometer cycle test have been
           demonstrated in some studies (13-17) whereas other studies have observed subnormal
           working capacity in these VSD patients (18-20). The most recent study, demonstrated
           significantly lower cardiopulmonary exercise capacity (9), a lower force frequency
           response (10), and abnormal ventilation pattern compared with healthy age and gender
           matched controls (11). How the abnormal pulmonary function interrelates with the
           impaired cardiac function and the limited exercise capacity remains to be clarified.
           None of the referred studies have explained the mechanism for the impaired exercise
           capacity. However, chronotropic incompetence (9,14,15,19,21) due to postsynaptic
           β-adrenergic desensitization of the cardiac autonomic nervous system after corrective
           cardiac surgery (14,15,19,21) have been suggested. Intrinsic sinus node dysfunction in
           postoperative congenital heart disease patients has also been demonstrated and may
           explains the lower exercise capacity (22,23). Moreover, abnormal pulmonary function has
           been demonstrated in these patients, which may be due to a direct mechanical limitation
           to breathing caused by the sternotomy the patient underwent earlier in life. However,
           there may also be an indirect physiological explanation to the abnormal exercise
           ventilation. A previous study found that the pulmonary function was somewhat decreased
           in many of the standard parameters, perhaps pointing in the direction of a direct
           mechanical restriction, but without any clear results(24). The study lacks a reference
           group of healthy controls, using standardized pulmonary values instead. Moreover, the
           patient group only consisted of children, not adults, making it difficult to predict the
           long-term outcome in this group of patients.

           β-adrenoceptors in heart (β1) and lungs (β2) are targets for catecholamine's causing
           stimulation of the sympathetic nervous system with among other effects bronchodilation
           and positive chronotropic, dromotropic, and ionotropic effects in the heart (25).
           Inhaled β2-agonists are commonly used as bronchodilators for patients conditioned with
           increased airway resistance (26). It has long been discussed if they have an ergogenic
           potential in sport due to both the effects on the lungs and a theoretical effect on the
           heart. It is now well described that exercise performance and maximal oxygen uptake
           (VO2-max) are not affected in healthy adults (27-29) not even when supratherapeutic
           doses of salbutamol are tested (27). However, these studies were mainly performed in
           athletes and not on the general population. In patients with chronic cor pulmonale a
           moderate chronotropic effect from β2-agonist infusions have been demonstrated (30). The
           effect in patients with congenital heart disease such as VSD is unknown. Since the VSD
           patients have an impaired pulmonary function as well as an impact on their chronotropic
           and ionotropic function, they might benefit from treatment of β2-agonists.

        2. Hypotheses

           A) Patients with surgically corrected VSD have an increased airway resistance at rest
           which is positively affected by inhaled β2-agonists.

           B) Patients with surgically corrected VSD have impaired spirometry outcomes which is
           positively affected by inhaled β2-agonists.

           C) Patients with surgically corrected VSD have an inferior diffusion lung capacity
           compared with un-operated VSD-patients and healthy controls.

           D) β2-agonists increase peak exercise minute ventilation and thereby the cardiopulmonary
           exercise capacity of surgically corrected VSD patients compared to un-operated
           VSD-patients and healthy controls.

           E) Inhaled β2-agonists increase peak exercise heart rate and thereby the cardiopulmonary
           exercise capacity of patients with surgically corrected VSD compared to un-operated
           VSD-patients and healthy controls.

           F) Patients with surgically corrected VSD have a reduced heart rate variability,
           compared with un-operated VSD-patients and healthy controls, that is positively affected
           by β2-agonists.

        3. Trial design

           The intended study will be conducted as a randomized controlled blinded cross over
           study, on the two VSD groups, matched with an equivalent number of controls. When
           written informed consent is obtained from participants they will be included in the
           trial. They will undergo two test days with an interval of at least of 48 hours and
           maximal 14 days, to ensure complete physical recovery and comparable physical condition
           at the two tests.

           It will be randomized whether the participant receives the Ventoline or the placebo at
           their first or second test day. To ensure similar test performances, both the
           participants and monitoring staff will be blinded in regards to what they are testing.
           For further information regarding study population see Chapter "Study Design" and "Arms
           and Investigations".

        4. Methods

           The tests below are described in the order that they are supposed to be conducted. Each
           test will be performed on both test days at Aarhus University Hospital, Skejby at The
           Department of Cardiothoracic and Vascular Surgery.

           4.1 Bioelectrical impedance analysis (Bioimpedance)

           The data collected are Total Body Water (TBW), Extracellular Fluid (ECF), Intracellular
           Fluid (ICF), Fat Free Mass (FFM) and Fat Mass (FM).

           4.2 Lung Clearance Index

           The equipment will analyse LCI 2,5 (LCI is defined as the cumulative expired volume
           (CEV) divided by the functional residual capacity (FRC) ), Scond (ventilation
           heterogeneity generated in the conductive lung zone) and Sacin (ventilation
           heterogeneity generated peripheral to the acinar entrance.

           4.3 Plethysmography (Static lung function)

           The equipment determine different lung parameters of which we will measure total lung
           capacity (TLC, liters), residual volume (RV, liters), functional residual capacity
           (FRCpleth, ml) and specific airway resistance (sRAW, kPa/sec) (35).

           4.4 Spirometry

           The test will include forced expiratory volume in one second (FEV1), forced vital
           capacity (FVC), the ratio between the two volumes (FEV1/FVC) and peak expiratory flow
           (PEF).

           4.5 Diffusion capacity test

           The diffusion capacity test will be performed on the same equipment as the
           plethysmography. The test determines lung carbon monoxide diffusion capacity (DLCO) and
           alveolar volume (VA) expressed as percentage of expected value.

           4.6 Impulse oscillometry

           The equipment will then be able to analyse resistance in of the respiratory system at 5
           Hz (R5), and at 20 Hz (R20) and the difference between the two measured resistances
           (Diff 5-20) (38,39).

           4.7 Holter-Monitorisation

           ECG activity during and after orthostatic and exercise testing will be monitored with a
           2-channel Holter monitor. Participants will be wearing the Holter-Monitors for 48 hours
           after activation at the first visit and for 24 hours after activation at the second
           visit. This results in 3 data-files:

           With the Pathfinder analysis software, we will assess any ECG changes and heart rate
           variability (HRV) during and after each exercise test. Endpoints are HRV (beat-to-beat
           variation) and mediterranean hour pulse.

           4.8 Orthostatic stress test (active standing)

           During the test we will measure blood pressure and heart rate with an automated
           sphygmomanometer on the left forearm.

           4.9 Exercise testing

           Exercise capacity will be tested on a Lode Corival ® ergometer cycle. With the Jaeger
           MaesterScreen CPX software system, we will monitor pulmonary ventilation and gas
           exchange in a breath-by-breath measurement. During test sessions, heart rate, blood
           pressure and electrocardiogram, will be measured continuously. The Holter-monitor is
           also recording during the exercise test.

           Each test day lasts approximately 4-5 hours.

        5. Statistics

           If suitable, continuous data will be reported as mean ± standard deviation (SD),
           otherwise they will be displayed as median value with 95% confidence intervals (CIs).
           Comparison of continuous data will be by unpaired Student's t-tests or, for
           non-normal-distributed data, the Mann-Whitney-Wilcoxon rank sum test. All correlations
           will be checked with simple regression analyses. Data from all included participants
           will be used for the statistical analyse. If correlations are made with the data
           material it will be evident on the published material. Data analysis will be performed
           with Stata/ IC 12.1 for Mac (StataCorp, Texas, United States of America).

           5.1. Power calculation

           Our main hypothesis is that β2-agonists increase peak exercise oxygen uptake to the same
           level as healthy controls. Previously, the same cohort of VSD patients was exercise
           tested in another study and in terms of peak oxygen uptake a statistically and
           clinically significant difference was found compared with controls; 38.0 ± 8.2 ml kg-1
           min-1 vs. 47.7 ± 6.5 ml kg-1 min-1 9. If we assume a true difference of approximately
           75% with the current endpoint, and apply a statistical power of 90 % and a level of
           significance of 95 %, we therefore need to include 26 participants in each of the three
           group. We aim at including 30 participants in each group and a total study population of
           90 participants.

           Deviations in the statistics or power calculation will be evident in in published
           material.

        6. Data storage

           Each participant will be given an identification number used for all purposes. A list
           over identification codes and complete name, address and telephone number will be saved
           and securely stored with the Trial Master File (TMF) and in REDCap. Data will be stored
           for 10 years. All digitalised data will be stored on two harddrives - one portable
           external harddrive that is kept safe behind two locked doors at the department and one
           external server named REDCap with continous back-up. Each identification number will
           have a Case Report Form (CRF) that also holds printed trial documents. Physical
           documents will be stored behind two locked doors and the CRF will be stored with the
           TMF.

           A source datasheet for the information noted in the CRF will be stored with the TMF. It
           will hold information on the origin of source data concerning, inclusion and exclusion,
           randomisation, bioimpedance data, Lung function data, Holter-Recordings and
           Holter-Recording analyses data, orthostatic stress test data and Exercise testing data.

        7. Ethical concerns

      The study is conducted in accordance with the Helsinki declaration and Danish law.

      The project will obtain permission from the Danish Protection Agency, the Danish Health and
      Medicines Authority, and The Central Denmark Region Committees on Health Research Ethics.
      Data will be handled in agreement with the personal data handling law and the participants'
      safety is always the number one priority during this trial.

      The project will be supervised by the department of Good Clinical Practice (the GCP-Unit).
    

Intervention name(s): Salbutamol; Norflouran (Placebo Evohaler(R) )
Intervention type(s): Drug; Drug
Intervention description(s): Ventoline(R), inhalation spray, 0,1 mg/dose, 9 doses administered as coherent single doses.; Placebo Evohaler(R) MDI, inhalation spray, 60 mg/dose, 9 doses administered as coherent single doses.
Other intervention name(s): Ventoline; Placebo
Intervention MeSH terms: Albuterol
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Congenital Heart Disease; Ventricular Septal Defect; Beta-2-agonists; Surgery; Follow-up