Ignite Creation Date:
2024-05-06 @ 8:38 AM
Last Modification Date:
2024-10-26 @ 12:02 PM
Study NCT ID:
NCT02782052
Status:
WITHDRAWN
Last Update Posted:
2020-01-29
First Post:
2016-05-17
Brief Title:
Bronchodilators Effects on Exertional Dyspnoea in Pulmonary Arterial Hypertension
Sponsor:
Assistance Publique - Hôpitaux de Paris
Organization:
Assistance Publique - Hôpitaux de Paris
Study Overview
Official Title:
Bronchodilators Effects on Exertional Dyspnoea in Pulmonary Arterial Hypertension
Status:
WITHDRAWN
Status Verified Date:
2020-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Sponsors decision
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
BD-HTAP
Brief Summary:
Activity-related dyspnoea appears to be the earliest and the most frequent complaint for which patients with PAH seek medical attention This symptom progresses relentlessly with time leading invariably to avoidance of activity with consequent skeletal muscle deconditioning and an impoverished quality of life Unfortunately effective management of this disabling symptom awaits a better understanding of its underlying physiology Our team has recently showed that PAH patients may exhibit reduced expiratory flows at low lung volumes at spirometry namely instantaneous forced expiratory flows measured after 50 and 75 of the FVC has been exhaled FEF50 and FEF75 lower than predicted despite a preserved forced expiratory volume in 1 secondforced vital capacity ratio FEV1FVC Several studies have shown that such a finding small airway disease could be common in certain PAH cohorts have either related it to incidental descriptions of airway wall thickening with lymphocytic infiltration in PAH or proposed several other speculative explanatory mechanisms either biological or mechanical Whatever its cause reduced expiratory flows at low lung volumes imply that the operating tidal volume VT range becomes closer than normally to residual volume RV mostly through an increase in RV elevated residual volumetotal lung capacity ratio RVTLC The reduced difference between forced and tidal expiratory flows promotes dynamic lung hyperinflation ie a progressive increase in end-expiratory lung volume EELV under conditions of increased ventilatory demand Dynamic lung hyperinflation DH is well known to have serious sensory consequences ie increase in dyspnoea intensity as clearly shown in patients with chronic obstructive pulmonary disease and chronic heart failure The aim of this study is to evaluate whether administration of inhaled BDs β2-agonist andor anticholinergic as add-ons to vasodilators would be beneficial to PAH patients by reducing andor delaying the rate of onset of DH thus ameliorating the exertional symptoms in patients with stable PAH undergoing high-intensity constant work-rate CWR cycle endurance test
This is a randomised double-blind placebo-controlled crossover study Design 5 visits V1 screening familiarization incremental cardiopulmonary exercise testing CPET V2 constant work-rate CWR-CPET V3 V4 and V5 CWR-CPET after intervention in a random order Placebo P Ipratropium Bromide IB Ipratropium Bromide Salbutamol IBSALB
This is a randomised double-blind placebo-controlled crossover study Design 5 visits V1 screening familiarization incremental cardiopulmonary exercise testing CPET V2 constant work-rate CWR-CPET V3 V4 and V5 CWR-CPET after intervention in a random order Placebo P Ipratropium Bromide IB Ipratropium Bromide Salbutamol IBSALB
Detailed Description:
Pulmonary arterial hypertension PAH defined as a mean pulmonary arterial pressure mPAP of 25 mmHg at rest and pulmonary arterial wedge pressure 15 mmHg is consistently associated with reduced exercise capacity and intolerable dyspnoea respiratory difficulty on exertion Dyspnoea is a complex multifaceted and highly personalized sensory experience the source and mechanisms of which are incompletely understood Activity-related dyspnoea appears to be the earliest and the most frequent complaint for which patients with PAH seek medical attention This symptom progresses relentlessly with time leading invariably to avoidance of activity with consequent skeletal muscle deconditioning and an impoverished quality of life Unfortunately effective management of this disabling symptom awaits a better understanding of its underlying physiology Previous studies on mechanisms of exertional dyspnoea in PAH have largely and mostly focused on the cardiovascular determinants of respiratory discomfort However respiratory mechanics abnormalities could contribute to exertional dyspnoea in these patients For instance PAH patients may exhibit reduced expiratory flows at low lung volumes at spirometry namely instantaneous forced expiratory flows measured after 50 and 75 of the FVC has been exhaled FEF50 and FEF75 lower than predicted despite a preserved forced expiratory volume in 1 secondforced vital capacity ratio FEV1FVC Several studies have shown that such a finding small airway disease could be common in certain PAH cohorts have either related it to incidental descriptions of airway wall thickening with lymphocytic infiltration in PAH or proposed several other speculative explanatory mechanisms either biological or mechanical Whatever its cause reduced expiratory flows at low lung volumes imply that the operating tidal volume VT range becomes closer than normally to residual volume RV mostly through an increase in RV elevated residual volumetotal lung capacity ratio RVTLC The reduced difference between forced and tidal expiratory flows promotes dynamic lung hyperinflation ie a progressive increase in end-expiratory lung volume EELV under conditions of increased ventilatory demand Dynamic lung hyperinflation DH increases the mechanical inspiratory load that the respiratory muscles must overcome to produce ventilation VE places the diaphragm at mechanical disadvantage and reduces the ability of VT to expand appropriately during exercise thus imposing restrictive mechanics VT is therefore truncated from below by the increasing EELV and constrained from above by the total lung capacity TLC envelope and the relatively reduced inspiratory reserve volume IRV Dynamic hyperinflation-induced critical mechanical constraint of VT expansion has serious sensory consequences ie increase in dyspnoea intensity as clearly shown in patients with chronic obstructive pulmonary disease and chronic heart failure
In this regard our team has recently confirmed that small airway dysfunction at spirometry exists in the majority of PAH patients 60 despite preserved FEV1VC and that this promotes the development of DH under the increased ventilatory demand in response to physical task in fact during the accelerated ventilatory response to exercise 60 of PAH patients did increase their EELV ie DH by an average of 050L from rest to peak exercise whereas age- and sex-matched healthy subjects did decrease it by an average of 045L Similar levels of DH have been reported in healthy subjects between 40 and 80 years of age patients with mild-to-severe COPD CHF and recently also in a heterogeneous group of patients with precapillary pulmonary hypertension but at much lower VE and work-rate than in our more homogeneous group of PAH patients Our team did also show that DH had serious sensory consequences for PAH patients DH imposed severe mechanical constraints on VT expansion during exercise on a background of progressively increasing central neural drive VT was truncated from below by the increasing EELV and constrained from above by the TLC envelope and the relatively reduced IRV It is generally accepted that in this setting dyspnoea results from the conscious awareness of the increasing disparity between respiratory effort or neural drive to breathe and simultaneous thoracic volume displacement The notion that DH and the subsequent constraint of VT expansion contributed to exertional dyspnoea was bolstered by the strong inverse correlation between dyspnoea intensity and both the increase dynamic EELVTLC R070 p005 and the reduced IRVTLC R-078 p005 at a standardized exercise stimulus
Our team was able for the first time to clearly demonstrate that an abnormal mechanics of breathing dynamic lung hyperinflation and the attendant constraint of VT expansion played an important role in dyspnoea causation in PAH during cycle exercise When increased ventilationperfusion mismatching is superimposed on pre-existing abnormal airway function greater troublesome exertional symptoms are the result This finding opens up new horizons for research in the field of dyspnoea mechanisms in PAH if investigator treats and ameliorates the lung function ie the respiratory mechanics abnormalities then our team could be able to improve the troublesome exertional symptoms that curtail daily-living activities of PAH patients The corollary of this is that any therapeutic intervention that effectively reduces andor delays the rate of onset of DH-induced critical ventilatory constraints such as administration of inhaled bronchodilators BDs as add-ons to vasodilators should have a positive effect on symptom perception in selected patients with stable PAH Determining the magnitude of this effect will be the object of the planned experiments However it should be borne in mind that the relationship between dyspnoea intensity and the severity of respiratory abnormalities is not linear but rather exponential In other words when a given disease is already responsible for a very intense dyspnoea a small additional deterioration directly or indirectly related to the disease can make dyspnoea intolerable Therefore even small BDs-induced changes in respiratory mechanics could have major effects on dyspnoea intensity on exertion in selected PAH patients which would undoubtedly have a major impact on their quality of life and their ability to perform daily-living activities
Hypothesis for the research What is the potential mechanism by which BDs would be able to ameliorate the exertional symptoms in patients with stable PAH and which BDs would be the best candidate in achieving that Regardless of the BDs administered our team anticipates that the potential mechanism by which BDs are able to ameliorate the exertional symptoms in patients with stable PAH would be the reduction andor delay of the rate of onset of DH-induced critical ventilatory constraints during exercise In contrast the nature of the specific BD β2-agonist or anticholinergic would be important in determining the mechanism by which the reduction in DH-induced critical ventilatory constraints can be achieved BDs have been extensively studied in COPD patients and to less extent in CHF patients Little is known in PAH patients Spiekerkoetter and colleagues have recently pointed out that inhaled β2-agonists are able to cause a mild but significant increase in resting FEV1 FEF50 and FEF75 in PAH patients They also showed that inhalation of β2-agonists determined a significant increase in resting cardiac output accompanied by an increase in stroke volume and a decrease in pulmonary and systemic vascular resistance in the presence of no change in heart rate To date no information is available on the effects of inhaled β2-agonists on the ventilatory mechanical and perceptual responses to exercise in PAH patients It can be argued that β2-agonists may reduce andor delay the rate of onset of DH-induced critical ventilatory constraints by 1 reducing the ventilatory demand in response to exercise andor by 2 modifying the shape and limits of the maximal flow-volume loop MFVL In the first case the improved cardiac function and concurrent ventilation-perfusion relations following β2-agonists would reduce the ventilatory demand thereby reducing the rate of DH and enhancing VT expansion during exercise This in turn would be expected to reduce the perceived exertional dyspnoea as clearly shown in patients with COPD following BDs In the second case β2-agonists would increase the maximal volume-corrected expiratory flow rates in the effort-independent mid-volume range where tidal breathing occurs ie increase in FEF50 and FEF75 as it has been shown in CHF This means that PAH patients would now accomplish the required alveolar ventilation at a lower operating lung volume and therefore at a reduced oxygen cost of breathing during exercise The corollary of this will be that PAH patients would increase their end-expiratory lung volume ie DH to less extent after inhalation of β2-agonist than before and this is likely to have salutary sensory consequences ie reduction in dyspnoea intensity for patients with PAH as clearly shown in patients with COPD Inhaled anticholinergic agents have not yet been studied neither at rest nor during exercise in PAH Inhalation of anticholinergic agents would increase the maximal volume-corrected expiratory flow rates in the effort-independent mid-volume range where tidal breathing occurs without interfering with the cardiac and pulmonary vascular functions as it has been shown in patients with CHF The attendant increase in FEF50 and FEF75 where tidal breathing occurs following inhaled anticholinergic agents would cause VT to be accommodated at a lower operating lung volume thus reducing the extent of DH and the concurrent ventilatory constraints imposed by the accelerated ventilatory response to exercise This in turn is likely to have salutary sensory consequences ie reduction in dyspnoea intensity for patients with PAH The interest of our study in dyspnoea evaluation after BDs in PAH patients is therefore evident and appealing for at least two reasons 1 there is no information in the literature about the effect of pharmacological interventions on dyspnoea intensity measured by Borg score during cycle exercise in PAH population and 2 investigators do not know how much will the dyspnoea intensity measured by Borg score change after BD administration in PAH population because no Minimally Clinically Important Difference MCID has been established for measurements of dyspnoea intensity Nonetheless based on COPD studies short-term post-intervention changes in dyspnoea intensity of 1 Borg unit at a standardized exercise time or VE appear to be clinically meaningful therefore our team can assume that this MCID may also apply to PAH patients undergoing cycle exercise testing after BD interventions
In this regard our team has recently confirmed that small airway dysfunction at spirometry exists in the majority of PAH patients 60 despite preserved FEV1VC and that this promotes the development of DH under the increased ventilatory demand in response to physical task in fact during the accelerated ventilatory response to exercise 60 of PAH patients did increase their EELV ie DH by an average of 050L from rest to peak exercise whereas age- and sex-matched healthy subjects did decrease it by an average of 045L Similar levels of DH have been reported in healthy subjects between 40 and 80 years of age patients with mild-to-severe COPD CHF and recently also in a heterogeneous group of patients with precapillary pulmonary hypertension but at much lower VE and work-rate than in our more homogeneous group of PAH patients Our team did also show that DH had serious sensory consequences for PAH patients DH imposed severe mechanical constraints on VT expansion during exercise on a background of progressively increasing central neural drive VT was truncated from below by the increasing EELV and constrained from above by the TLC envelope and the relatively reduced IRV It is generally accepted that in this setting dyspnoea results from the conscious awareness of the increasing disparity between respiratory effort or neural drive to breathe and simultaneous thoracic volume displacement The notion that DH and the subsequent constraint of VT expansion contributed to exertional dyspnoea was bolstered by the strong inverse correlation between dyspnoea intensity and both the increase dynamic EELVTLC R070 p005 and the reduced IRVTLC R-078 p005 at a standardized exercise stimulus
Our team was able for the first time to clearly demonstrate that an abnormal mechanics of breathing dynamic lung hyperinflation and the attendant constraint of VT expansion played an important role in dyspnoea causation in PAH during cycle exercise When increased ventilationperfusion mismatching is superimposed on pre-existing abnormal airway function greater troublesome exertional symptoms are the result This finding opens up new horizons for research in the field of dyspnoea mechanisms in PAH if investigator treats and ameliorates the lung function ie the respiratory mechanics abnormalities then our team could be able to improve the troublesome exertional symptoms that curtail daily-living activities of PAH patients The corollary of this is that any therapeutic intervention that effectively reduces andor delays the rate of onset of DH-induced critical ventilatory constraints such as administration of inhaled bronchodilators BDs as add-ons to vasodilators should have a positive effect on symptom perception in selected patients with stable PAH Determining the magnitude of this effect will be the object of the planned experiments However it should be borne in mind that the relationship between dyspnoea intensity and the severity of respiratory abnormalities is not linear but rather exponential In other words when a given disease is already responsible for a very intense dyspnoea a small additional deterioration directly or indirectly related to the disease can make dyspnoea intolerable Therefore even small BDs-induced changes in respiratory mechanics could have major effects on dyspnoea intensity on exertion in selected PAH patients which would undoubtedly have a major impact on their quality of life and their ability to perform daily-living activities
Hypothesis for the research What is the potential mechanism by which BDs would be able to ameliorate the exertional symptoms in patients with stable PAH and which BDs would be the best candidate in achieving that Regardless of the BDs administered our team anticipates that the potential mechanism by which BDs are able to ameliorate the exertional symptoms in patients with stable PAH would be the reduction andor delay of the rate of onset of DH-induced critical ventilatory constraints during exercise In contrast the nature of the specific BD β2-agonist or anticholinergic would be important in determining the mechanism by which the reduction in DH-induced critical ventilatory constraints can be achieved BDs have been extensively studied in COPD patients and to less extent in CHF patients Little is known in PAH patients Spiekerkoetter and colleagues have recently pointed out that inhaled β2-agonists are able to cause a mild but significant increase in resting FEV1 FEF50 and FEF75 in PAH patients They also showed that inhalation of β2-agonists determined a significant increase in resting cardiac output accompanied by an increase in stroke volume and a decrease in pulmonary and systemic vascular resistance in the presence of no change in heart rate To date no information is available on the effects of inhaled β2-agonists on the ventilatory mechanical and perceptual responses to exercise in PAH patients It can be argued that β2-agonists may reduce andor delay the rate of onset of DH-induced critical ventilatory constraints by 1 reducing the ventilatory demand in response to exercise andor by 2 modifying the shape and limits of the maximal flow-volume loop MFVL In the first case the improved cardiac function and concurrent ventilation-perfusion relations following β2-agonists would reduce the ventilatory demand thereby reducing the rate of DH and enhancing VT expansion during exercise This in turn would be expected to reduce the perceived exertional dyspnoea as clearly shown in patients with COPD following BDs In the second case β2-agonists would increase the maximal volume-corrected expiratory flow rates in the effort-independent mid-volume range where tidal breathing occurs ie increase in FEF50 and FEF75 as it has been shown in CHF This means that PAH patients would now accomplish the required alveolar ventilation at a lower operating lung volume and therefore at a reduced oxygen cost of breathing during exercise The corollary of this will be that PAH patients would increase their end-expiratory lung volume ie DH to less extent after inhalation of β2-agonist than before and this is likely to have salutary sensory consequences ie reduction in dyspnoea intensity for patients with PAH as clearly shown in patients with COPD Inhaled anticholinergic agents have not yet been studied neither at rest nor during exercise in PAH Inhalation of anticholinergic agents would increase the maximal volume-corrected expiratory flow rates in the effort-independent mid-volume range where tidal breathing occurs without interfering with the cardiac and pulmonary vascular functions as it has been shown in patients with CHF The attendant increase in FEF50 and FEF75 where tidal breathing occurs following inhaled anticholinergic agents would cause VT to be accommodated at a lower operating lung volume thus reducing the extent of DH and the concurrent ventilatory constraints imposed by the accelerated ventilatory response to exercise This in turn is likely to have salutary sensory consequences ie reduction in dyspnoea intensity for patients with PAH The interest of our study in dyspnoea evaluation after BDs in PAH patients is therefore evident and appealing for at least two reasons 1 there is no information in the literature about the effect of pharmacological interventions on dyspnoea intensity measured by Borg score during cycle exercise in PAH population and 2 investigators do not know how much will the dyspnoea intensity measured by Borg score change after BD administration in PAH population because no Minimally Clinically Important Difference MCID has been established for measurements of dyspnoea intensity Nonetheless based on COPD studies short-term post-intervention changes in dyspnoea intensity of 1 Borg unit at a standardized exercise time or VE appear to be clinically meaningful therefore our team can assume that this MCID may also apply to PAH patients undergoing cycle exercise testing after BD interventions
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 2014-002590-10 | EUDRACT_NUMBER | None | None |