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

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ClinicalTrials.gov Identifier: NCT01116063
Recruitment Status : Unknown
Verified May 2010 by Carmel Medical Center.
Recruitment status was:  Not yet recruiting
First Posted : May 4, 2010
Last Update Posted : May 4, 2010
Sponsor:
Information provided by:
Carmel Medical Center

Tracking Information
First Submitted Date  ICMJE May 3, 2010
First Posted Date  ICMJE May 4, 2010
Last Update Posted Date May 4, 2010
Study Start Date  ICMJE May 2010
Estimated Primary Completion Date January 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 3, 2010)
Pulmonary vascular resistance [ Time Frame: 6 months ]
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: May 3, 2010)
  • 6 minutes walking test [ Time Frame: 6 months ]
  • Borg dyspnea score [ Time Frame: 6 months ]
  • NT-BNP [ Time Frame: 6 months ]
  • Arterial blood gases [ Time Frame: 6 months ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Inhaled Iloprost for Disproportionate Pulmonary Hypertension in Chronic Obstructive Pulmonary Disease (COPD)
Official Title  ICMJE Inhaled Iloprost for Disproportionate Pulmonary Hypertension in Chronic Obstructive Pulmonary Disease
Brief 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

Detailed 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Chronic Obstructive Pulmonary Disease
Intervention  ICMJE Drug: Inhaled iloprost
Inhalation Initial: 2.5 mcg/dose; if tolerated, increase to 5 mcg/dose; administer 6 times daily
Other Name: Brand name - Ventavis
Study Arms  ICMJE Experimental: Single arm open label
All patients will receive the study drugs and will be evaluated
Intervention: Drug: Inhaled iloprost
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Unknown status
Estimated Enrollment  ICMJE
 (submitted: May 3, 2010)
15
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 2013
Estimated Primary Completion Date January 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 25 Years to 90 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Israel
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01116063
Other Study ID Numbers  ICMJE COPDVEN 2009
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Yochai Adir, Director pulmonary hypertesnion service, Pulmonary divison Carmel Medical Center
Study Sponsor  ICMJE Carmel Medical Center
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Yochai Adir, MD Pulmoanry Division, Carmel Medical Center
PRS Account Carmel Medical Center
Verification Date May 2010

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP