Effect of Sildenafil on Diffusion Capacity in Patients With PH and Parenchymal Lung Disease

• ClinicalTrials.gov Identifier: NCT01948518
• Recruitment Status: Completed
• First Posted: September 23, 2013
• Results First Posted: September 30, 2014
• Last Update Posted: September 30, 2014
• Sponsor: The Cleveland Clinic
• Information provided by (Responsible Party): Umur Hatipoglu, MD, The Cleveland Clinic

Study Description

Brief Summary:

The purpose of this study was to investigate the acute effects of sildenafil on diffusion capacity, a commonly performed pulmonary function test, which is used to assess the lungs' gas exchange capability.

This study does not assess safety or efficacy of the drug. The study does not have clinical end points. The variables studied are diffusion capacity and 6 minute walk after a single dose of sildenafil.

This study has been completed.

Condition or disease	Intervention/treatment	Phase
Diffuse Parenchymal Lung Disease; Pulmonary Hypertension	Drug: Oral sildenafil 20 mg	Not Applicable

Detailed Description:

Sildenafil is a cyclic GMP selective phosphodiesterase type 5 inhibitor approved for use by the FDA in patients with pulmonary arterial hypertension. There has been recent interest in the use of the drug in patients with diffuse parenchymal lung diseases. This is largely based on sildenafil's salutary effects observed in small studies (Collard et al. 897-99;Ghofrani et al. 895-900;Collard et al. 897-99) and the frequent coexistence of pulmonary hypertension in these patients (Nathan et al. 657-63). In eight patients with pulmonary fibrosis and pulmonary hypertension, sildenafil reduced pulmonary artery pressure and improved shunt fraction as determined by multiple inert gas elimination technique (Ghofrani et al. 895-900;Nathan et al. 657-63). Collard et al demonstrated a 49 meter improvement in 6 minute walk distance in 11 patients with idiopathic pulmonary fibrosis and pulmonary hypertension after 3 months of therapy with sildenafil.

Main theoretical concern with the use of pulmonary arterial vasodilator therapy has been worsening of ventilation perfusion matching due to release of hypoxic vasoconstriction. Such a phenomenon is well recognized during prostacyclin infusion(Ghofrani et al. 895-900;Walmrath et al. 1084-92). Inhaled route seems to circumvent this side effect by preferentially delivering the drug to the alveoli with high V/Q ratios and augmenting blood flow to these regions (Ghofrani et al. 895-900;Walmrath et al. 1084-92). In the only study to address possible effect of systemically administered sildenafil on gas exchange, Ghofrani et al observed improvement in V/Q matching in eight patients using the multiple inert gas elimination technique (MIGET). The authors postulated an enhancement of local defense mechanisms against hypoxia i.e. increased nitric oxide availability to hypoxic alveoli despite oral route of administration(Ghofrani et al. 895-900). In a recent study of 14 normal subjects, oral sildenafil did not effect DLCO measurements at rest, after exercise and under hypoxic conditions(Snyder et al. 421-30).

Diffusion capacity of the lung for carbon monoxide (DLCO) is the clinically available method of assessing gas exchange for practitioners. It is frequently used as a tool for serial monitoring of diffuse parenchymal lung disease. American Thoracic Society has endorsed its use in the assessment of patients with idiopathic interstitial pneumonias(American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias . This Joint Statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS Board of Directors, June 2001 and by The ERS Executive Committee, June 2001 277-304).

The aim of our study was to delineate the effects of orally administered sildenafil on diffusion capacity (absolute value). The significance of this information was twofold. First, it would be helpful clinically to determine the contribution of a pulmonary vasodilator to the change in DLCO to separate this effect from a true clinical change. Second, sildenafil's effect on gas exchange may lead to modifications in therapy such as changes in oxygen flow delivered to patients.

This is not a study that measures clinical outcome or safety of sildenafil. A single dose was administered and effect on diffusion capacity and 6 minute walk were assessed compared to baseline. While we would caution clinicians for rare exceptions to these findings, we believe our data exclude a significant confounding effect in interpretation of diffusion capacity in patients with parenchymal lung disease who are treated for pulmonary hypertension with oral sildenafil. Whether this conclusion holds true at higher doses of sildenafil and in patients with vasodilator response may offer further venues for research.

We were asked to retrospectively register the study at the request of BMC Pulmonary Medicine Journal Editorial Office prior to publication.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 15 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Diagnostic
• Official Title: The Effect of Sildenafil on Diffusion Capacity Measurements in Patients With Pulmonary Hypertension and Parenchymal Lung Disease
• Study Start Date: June 2009
• Actual Primary Completion Date: June 2012
• Actual Study Completion Date: June 2012

Arms and Interventions

Arm	Intervention/treatment
Experimental: Oral sildenafil 20 mg; oral sildenafil, single dose at baseline	Drug: Oral sildenafil 20 mg; A single dose of sildenafil will be given after recording baseline diffusion capacity and 6 minute walk. Measurements will be repeated one hour after the drug.; Other Name: sildenafil

Outcome Measures

Primary Outcome Measures :

1. Change in Diffusion Capacity Measured at Baseline and One Hour. [ Time Frame: Baseline and one hour ]
   Determine the acute effect of oral sildenafil on diffusion capacity in patients with diffuse parenchymal lung disease and concomitant pulmonary hypertension

Secondary Outcome Measures :

1. Change in 6 Minute Walk Distance [ Time Frame: Baseline and one hour ]
   The change in 6 minutes walk distance from baseline one hour after receiving 20 mg of sildenafil orally will be measured.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Adult patients over age 18 years of age who are able to consent
• Diagnosis of diffuse parenchymal lung disease with concomitant pulmonary hypertension

Exclusion Criteria:

• None

Contacts and Locations

Locations

United States, Ohio

Cleveland Clinic

Cleveland, Ohio, United States, 44195

Sponsors and Collaborators

The Cleveland Clinic

Investigators

• Principal Investigator: Umur Hatipoglu, MD; The Cleveland Clinic

More Information

Publications:

Lettieri CJ, Nathan SD, Barnett SD, Ahmad S, Shorr AF. Prevalence and outcomes of pulmonary arterial hypertension in advanced idiopathic pulmonary fibrosis. Chest. 2006 Mar;129(3):746-52.

Hamada K, Nagai S, Tanaka S, Handa T, Shigematsu M, Nagao T, Mishima M, Kitaichi M, Izumi T. Significance of pulmonary arterial pressure and diffusion capacity of the lung as prognosticator in patients with idiopathic pulmonary fibrosis. Chest. 2007 Mar;131(3):650-656. doi: 10.1378/chest.06-1466. Epub 2007 Feb 22.

Ghofrani HA, Wiedemann R, Rose F, Schermuly RT, Olschewski H, Weissmann N, Gunther A, Walmrath D, Seeger W, Grimminger F. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial. Lancet. 2002 Sep 21;360(9337):895-900.

Badesch DB, Hill NS, Burgess G, Rubin LJ, Barst RJ, Galiè N, Simonneau G; SUPER Study Group. Sildenafil for pulmonary arterial hypertension associated with connective tissue disease. J Rheumatol. 2007 Dec;34(12):2417-22. Epub 2007 Nov 1.

Rubin LJ, Badesch DB, Fleming TR, Galiè N, Simonneau G, Ghofrani HA, Oakes M, Layton G, Serdarevic-Pehar M, McLaughlin VV, Barst RJ; SUPER-2 Study Group. Long-term treatment with sildenafil citrate in pulmonary arterial hypertension: the SUPER-2 study. Chest. 2011 Nov;140(5):1274-1283. doi: 10.1378/chest.10-0969. Epub 2011 May 5.

Idiopathic Pulmonary Fibrosis Clinical Research Network, Zisman DA, Schwarz M, Anstrom KJ, Collard HR, Flaherty KR, Hunninghake GW. A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis. N Engl J Med. 2010 Aug 12;363(7):620-8. doi: 10.1056/NEJMoa1002110. Epub 2010 May 18.

American Thoracic Society; European Respiratory Society. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. Am J Respir Crit Care Med. 2002 Jan 15;165(2):277-304. Review. Erratum in: Am J Respir Crit Care Med2002 Aug 1;166(3):426.

Miller A, Thornton JC, Warshaw R, Anderson H, Teirstein AS, Selikoff IJ. Single breath diffusing capacity in a representative sample of the population of Michigan, a large industrial state. Predicted values, lower limits of normal, and frequencies of abnormality by smoking history. Am Rev Respir Dis. 1983 Mar;127(3):270-7.

Macintyre N, Crapo RO, Viegi G, Johnson DC, van der Grinten CP, Brusasco V, Burgos F, Casaburi R, Coates A, Enright P, Gustafsson P, Hankinson J, Jensen R, McKay R, Miller MR, Navajas D, Pedersen OF, Pellegrino R, Wanger J. Standardisation of the single-breath determination of carbon monoxide uptake in the lung. Eur Respir J. 2005 Oct;26(4):720-35.

ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002 Jul 1;166(1):111-7. Erratum in: Am J Respir Crit Care Med. 2016 May 15;193(10):1185.

Kazerooni EA, Martinez FJ, Flint A, Jamadar DA, Gross BH, Spizarny DL, Cascade PN, Whyte RI, Lynch JP 3rd, Toews G. Thin-section CT obtained at 10-mm increments versus limited three-level thin-section CT for idiopathic pulmonary fibrosis: correlation with pathologic scoring. AJR Am J Roentgenol. 1997 Oct;169(4):977-83.

Collard HR, Anstrom KJ, Schwarz MI, Zisman DA. Sildenafil improves walk distance in idiopathic pulmonary fibrosis. Chest. 2007 Mar;131(3):897-899. doi: 10.1378/chest.06-2101.

Madden BP, Allenby M, Loke TK, Sheth A. A potential role for sildenafil in the management of pulmonary hypertension in patients with parenchymal lung disease. Vascul Pharmacol. 2006 May;44(5):372-6. Epub 2006 Mar 29.

Snyder EM, Olson TP, Johnson BD, Frantz RP. Influence of sildenafil on lung diffusion during exposure to acute hypoxia at rest and during exercise in healthy humans. Eur J Appl Physiol. 2008 Jul;103(4):421-30. doi: 10.1007/s00421-008-0735-5.

• Responsible Party: Umur Hatipoglu, MD, Staff Pulmonary, Allergy and Critical Care Medicine, The Cleveland Clinic
• ClinicalTrials.gov Identifier: NCT01948518
• Other Study ID Numbers: 08-993
• First Posted: September 23, 2013
• Results First Posted: September 30, 2014
• Last Update Posted: September 30, 2014
• Last Verified: July 2014

Keywords provided by Umur Hatipoglu, MD, The Cleveland Clinic:

Pulmonary hypertension; Parenchymal Lung Disease; Diffusion Capacity

Additional relevant MeSH terms:

Lung Diseases; Hypertension, Pulmonary; Lung Diseases, Interstitial; Hypertension; Vascular Diseases; Cardiovascular Diseases; Respiratory Tract Diseases; Sildenafil Citrate; Vasodilator Agents; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Urological Agents