Bronchodilator's Effects on Exertional Dyspnoea in Pulmonary Arterial Hypertension

• Status: Withdrawn
• Trial end date: 2019-02-01
• Target enrollment: 0
• Participant gender: All

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 second/forced vital capacity ratio (FEV1/FVC) . 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 volume/total lung capacity ratio, RV/TLC). The reduced difference between forced and tidal expiratory flows promotes dynamic lung hyperinflation [i.e., 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, i.e., 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 and/or anticholinergic), as add-ons to vasodilators, would be beneficial to PAH patients by reducing and/or 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 (IB+SALB).

• Phase: Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Assistance Publique - Hôpitaux de Paris
• Treatments: Albuterol; Bromides; Bronchodilator Agents; Ipratropium

Criteria

Inclusion Criteria:

1. Adult (> 18 years old);

2. With signed informed consent;

3. Affiliated to social security system;

4. With idiopathic or heritable PAH , diagnosed according to the current evidence-based clinical practice guidelines;

5. Irrespective of the treatment received;

6. Clinically stable during the 3 preceding months and the entire duration of the project;

7. With CPET scheduled within the frame of their clinical follow-up at the reference center.

Exclusion Criteria:

1. Pregnant women;

2. Past or current tobacco-smoking history;

3. A spirometric evidence of an obstructive ventilatory defect as defined by a reduced FEV1/VC ratio below the 5th percentile of the predicted value;

4. A FEF75% >60% of predicted normal values at spirometry;

5. A TLC below the 5th percentile of the predicted value;

6. A body mass index >30 kg.m-2;

7. Use of supplemental oxygen;

8. PAH induced by drugs and toxins;

9. PAH associated with other conditions, including connective tissue diseases, congenital heart diseases, portal hypertension, and HIV infection;

10. Chronic thromboembolic pulmonary hypertension;

11. Other respiratory, cardiac and other diseases that could contribute to dyspnoea or exercise limitation;

12. Contraindications to clinical exercise testing, such as NYHA functional class IV, syncope and others;

13. Specific contraindications (precautions and drug interactions) to the administration of IB or IB+SALB.