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Bronchodilator's Effects on Exertional Dyspnoea in Pulmonary Arterial Hypertension (BD-HTAP)

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ClinicalTrials.gov Identifier: NCT02782052
Recruitment Status : Active, not recruiting
First Posted : May 25, 2016
Last Update Posted : January 12, 2018
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

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 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).


Condition or disease Intervention/treatment Phase
Pulmonary Arterial Hypertension Drug: Nebulized ipratropium bromide Drug: Nebulized combination ipratropium bromide with salbutamol Drug: Nebulized Placebo Phase 3

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 18 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Bronchodilator's Effects on Exertional Dyspnoea in Pulmonary Arterial Hypertension
Study Start Date : July 2016
Estimated Primary Completion Date : October 2018
Estimated Study Completion Date : February 2019


Arm Intervention/treatment
Experimental: Nebulized ipratropium bromide
Administration in a random order nebulized ipratropium bromide at V3 or V4 or V5
Drug: Nebulized ipratropium bromide

Administration at V3 or V4 or V5 in a random order:

  • Placebo (P; sterile 0.9% sodium chloride solution)
  • Or nebulized ipratropium bromide (IB; 0.5mg/2mL) alone
  • Or nebulized combination ipratropium bromide with salbutamol (IB+SALB; 0.5mg/2mL + 2.5mg/2.5mL).

Experimental: Nebulized combination ipratropium bromide with salbutamol
Administration in a random order combination Ipratropium bromide and Salbutamol at V3 or V4 or V5
Drug: Nebulized combination ipratropium bromide with salbutamol

Administration at V3 or V4 or V5 in a random order:

  • Placebo (P; sterile 0.9% sodium chloride solution)
  • Or nebulized ipratropium bromide (IB; 0.5mg/2mL) alone
  • Or nebulized combination ipratropium bromide with salbutamol (IB+SALB; 0.5mg/2mL + 2.5mg/2.5mL).

Placebo Comparator: Placebo
Administration in a random order placebo at V3 or V4 or V5
Drug: Nebulized Placebo

Administration at V3 or V4 or V5 in a random order:

  • Placebo (P; sterile 0.9% sodium chloride solution)
  • Or nebulized ipratropium bromide (IB; 0.5mg/2mL) alone
  • Or nebulized combination ipratropium bromide with salbutamol (IB+SALB; 0.5mg/2mL + 2.5mg/2.5mL).




Primary Outcome Measures :
  1. Reduction of 1.0 unit of dyspnoea intensity (on a Borg scale) between pre-dose and post-dose BD measured at a standardized time (iso-time) or V'E (iso-V'E) [ Time Frame: At two month (V3), three month (V4) and three months (V5) ]
    At the end of CWR-CPET, the sensory-perceptual and affective dimensions of dyspnoea will be evaluated with Multidimensional Dyspnoea Profile (MDP) questionnaire.


Secondary Outcome Measures :
  1. Difference (BDs versus placebo) in CWR endurance time (60 seconds difference) will be also evaluated as potential index of improved exercise tolerance [ Time Frame: At two month (V3), three month (V4) and three months (V5) ]
    Change (increase) of at least 60 seconds in CWR-CPET endurance time between pre-dose and post-dose BD measured at the end of CWR bouts.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT02782052     History of Changes
Other Study ID Numbers: P130906
2014-002590-10 ( EudraCT Number )
First Posted: May 25, 2016    Key Record Dates
Last Update Posted: January 12, 2018
Last Verified: January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Assistance Publique - Hôpitaux de Paris:
pulmonary arterial hypertension
spirometry
dynamic lung hyperinflation
bronchodilator
dyspnoea
Idiopathic
heritable
PAH
Additional relevant MeSH terms:
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Familial Primary Pulmonary Hypertension
Dyspnea
Hypertension
Vascular Diseases
Cardiovascular Diseases
Hypertension, Pulmonary
Lung Diseases
Respiratory Tract Diseases
Respiration Disorders
Signs and Symptoms, Respiratory
Signs and Symptoms
Bromides
Albuterol
Bronchodilator Agents
Ipratropium
Anticonvulsants
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Tocolytic Agents
Reproductive Control Agents
Adrenergic beta-2 Receptor Agonists
Adrenergic beta-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Cholinergic Antagonists