Inhaled Iloprost for Disproportionate Pulmonary Hypertension in Chronic Obstructive Pulmonary Disease (COPD)

Chronic Obstructive Pulmonary Disease Clinical Trial

— COPDVEN  

Official title:

Inhaled Iloprost for Disproportionate Pulmonary Hypertension in Chronic Obstructive Pulmonary Disease

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT01116063
• Other study ID #: COPDVEN 2009
• Status: Not yet recruiting
• Phase: Phase 4
• First received: May 3, 2010
• Last updated: May 3, 2010
• Start date: May 2010
• Est. completion date: June 2013

Study information

• Verified date: May 2010
• Source: Carmel Medical Center
• Contact: Yochai aDIR, MD
• Phone: 972-4-8250517
• Email: yochaiad[@]clalit.org.il
• Is FDA regulated: No
• Health authority: Israel: Ministry of Health
• Study type: Interventional

Clinical Trial Summary

Pulmonary hypertension is frequently present in COPD and it is generally limited to a mild increase in mean pulmonary artery pressure. However some COPD patients are characterized by higher levels of mPAP at rest, fulfilling the definition of moderate or severe PH disproportionate PH .

In these patients the elevated pulmonary pressures adversely affect the prognosis.At the present time the evidence for the the use of specific pulmonary vasodilators in the management of these patients are scarce and cannot be recommended.the aim of this study is to evaluate the medium term efficacy and safety of the inhaled prostacyclin stable analog, iloprost in patients with COPD and moderate to severe pulmonary hypertension

Description:

While pulmonary hypertension is frequently present in COPD, particularly in the presence of hypoxemia, it is generally limited to a mild increase in mean pulmonary artery pressure in the face of a normal cardiac output.

Apart from this classical and widely observed profile of PH with modestly elevated mPAP, some COPD patients are characterized by higher levels of mPAP at rest, fulfilling the definition of moderate or severe PH . This kind of PH may be observed in patients presenting with a severe obstructive disease, but sometimes contrasts with a mild or moderate obstruction. In the latter case, the term disproportionate PH has been proposed, but it can be extended to describe all COPD patients with moderate to- severe PH.

Therefore, it is possible that in some patients with COPD, pulmonary hypertension contributes to the clinical picture because of right ventricular output limitation and is responsible for the poor prognosis of these patients, which is similar to that in primary pulmonary arterial hypertension.

The exact incidence of clinically significant pulmonary hypertension, defined as pulmonary hypertension that contributes to symptomatology and prognosis, is difficult to estimate in COPD. A prevalence of 5.8%- 13.5% in patients seems reasonable which would suggest an incidence of 1-3/10,000, which is 100 times the incidence of idiopathic pulmonary arterial hypertension.

These patients are characterized by marked effort dyspnea , profound hypoxemia, hypocapnia, moderate airway obstruction and a very low DLCO.

PH in COPD was an independent prognostic factor. Indeed, patients with similar airflow limitation had lower life expectancy when PH was resent. Patients with PH had a significantly lower survival rate at 5 yrs compared with patients without PH (33 versus 66%). Pathologic studies that stemmed from long-term oxygen trials pointed to the fact that pulmonary vascular remodeling in chronic obstructive pulmonary disease (COPD) is more than just medial hypertrophy from long-lasting hypoxic vasoconstriction. In these patients, all vessel wall layers appear to be involved, with intimal changes actually being the most prominent. Major remodeling of all pulmonary arterial vessel layers explains why pulmonary hypertension in COPD is often not,or minimally, reversible by supplemental oxygen, acutely or chronically. The pathobiology of pulmonary artery remodeling in advanced COPD remains incompletely explored. There are data supporting an endothelium-derived vasoconstrictor-dilator imbalance, mainly from a decreased endothelial nitric oxide expression. Plasma levels of ET-1 are increased both in patients with severe COPD and there is evidence that ETA and ETB receptor expression is increased in the pulmonary arteries of patients with COPD.

The major unmet medical need is the absence of a simple drug therapy that relieves the breathlessness or muscle fatigue, reduces pulmonary vascular resistance and the overloaded right ventricles that severely limits exercise tolerance in COPD and affects survival.

The only validated therapeutic approach of the 'common' PH in COPD patients is long-term oxygen therapy. A large variety of vasodilators has been tested in numerous studies both after short- and medium-term administration. The early enthusiasm vanished subsequently for several reasons: modesty of the vasodilator effect, inability for some drugs to sustain the acute benefit, no specificity of the vasodilator effect with concomitant systemic vasodilatation, deleterious effect on gas exchange due to a diminution of the ventilation/perfusion ratio and no demonstration of a survival benefit. At the present time vasodilators cannot be recommended in the management of COPD.

Treatments of PAH have shown a dramatic change in the past few years. Synthetic prostacyclin (epoprostenol), prostacyclin analogues, endothelin-1 receptor antagonists and phosphodiesterase-5 inhibitors are in use in group I PAH with improve clinical outcome.

Based on analogy to primary pulmonary hypertension, a specific interventions aiming at the restoration of endothelial vasoconstrictor- dilator imbalance could be undertaken.

Selective pulmonary vasodilatation by inhalation of the vasorelaxant agent is an appealing concept to circumvent some of the hazards inherent in systemic vasodilator therapy in COPD patients with PH. Treatment of these patients with aerosolization of iloprost may reduce pulmonary vascular resistance , increases cardiac output while conserving ventilation-perfusion matching and and shunt preventing worsening of arterial hypoxia and wasting of the small ventilatory reserve of these patients.

In order to resolve these uncertainties we suggest evaluating the effectiveness of an inhaled iloprost in COPD patients with moderate to severe pulmonary hypertension. This evaluation would include monitoring and measurement of all the relevant cardio-respiratory variables as set out in detail below.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 15
• Est. completion date: June 2013
• Est. primary completion date: January 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 25 Years to 90 Years

Eligibility

Inclusion Criteria:

1. Patient with COPD and increased SPAP >55 on echocardiogram will be screened for the study.

2. Patients with normal wedge pressure ( [PCWP] = 15 mm Hg), mean PAP = 35 mm Hg and a pulmonary vascular resistance (PVR- 3.0 wood unit)on right heart catheterization.

3. Diagnosis of COPD according to GOLD guidelines

4. The patient can read, understand and sign the informed consent.

Exclusion Criteria:

1. Other identified cause for pulmonary hypertension

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Obstructive Pulmonary Disease
• Hypertension
• Hypertension, Pulmonary
• Lung Diseases
• Lung Diseases, Obstructive
• Pulmonary Disease, Chronic Obstructive

Intervention

Drug:
• Inhaled iloprost
Inhalation Initial: 2.5 mcg/dose; if tolerated, increase to 5 mcg/dose; administer 6 times daily

Locations

Country	Name	City	State
Israel	Pulmoanry Division, Carmel Medical Center	Haifa

Sponsors (1)

Lead Sponsor	Collaborator
Carmel Medical Center

Country where clinical trial is conducted

Israel, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Pulmonary vascular resistance		6 months	No
Secondary	6 minutes walking test		6 months	No
Secondary	Borg dyspnea score		6 months	No
Secondary	NT-BNP		6 months	No
Secondary	Arterial blood gases		6 months	Yes