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Targeting Vascular Reactivity in Idiopathic Pulmonary Fibrosis

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ClinicalTrials.gov Identifier: NCT00981747
Recruitment Status : Terminated (Funding was withdrawn.)
First Posted : September 22, 2009
Results First Posted : November 12, 2018
Last Update Posted : November 12, 2018
Sponsor:
Collaborator:
Pulmonary Fibrosis Foundation
Information provided by (Responsible Party):
Alicia Gerke, University of Iowa

Brief Summary:
The purpose of this study is to determine whether combination therapy with sildenafil and losartan can improve function and exercise tolerance in patients with idiopathic pulmonary fibrosis.

Condition or disease Intervention/treatment Phase
Idiopathic Pulmonary Fibrosis Pulmonary Fibrosis Drug: Sildenafil Drug: Losartan Drug: Sildenafil and Losartan Drug: Placebo Oral Tablet Phase 2 Phase 3

Detailed Description:

It is currently suspected that the fibrosis in IPF is based upon an abnormal reparative process in the lung. Normally, an insult to the endothelium or epithelium of the lung would trigger an inflammatory process to help repair the site of injury; epithelial and endothelial cells then replicate and repair the tissue damage. In pulmonary fibrosis, alterations in this cascade change the balance of the inflammatory products and reduce the regulatory response which can produce continued inflammation. Fibrosis results from continued deposition of collagen by proliferating fibroblasts and lack of collagen breakdown.

In addition to fibrosis and microvascular destruction, pulmonary hypertension in IPF patients is a significant contributor to morbidity and mortality. The prevalence ranges from 32-85%, suggesting that pulmonary vascular disease is one of several processes that contribute to severity of disease.

We propose use of two therapeutic agents that affect the balance of vasoconstriction and vasodilation to improve basal tone of the vasculature. First, we propose the use of a phosphodiesterase inhibitor. Sildenafil (Viagra, Revatio) is an orally administered vasodilator that prolongs the effect of nitric oxide by inhibiting phosphodiesterase type 5 (PDE-5) which is responsible for degradation of cGMP. Increased cGMP concentration results in pulmonary vasculature relaxation and consequent vasodilation. Second, the use of an angiotensin receptor blocker (ARB) acts to diminish the direct vasoconstrictor effect of angiotensin and endothelin-1 in the vessels. In treatment of systemic hypertension, ARBs have been shown to be associated with a decrease in the amount of circulating endothelin-1 and increase in basal nitric oxide release. They have also been shown to rapidly inhibit the generation of reactive oxygen species by inflammatory cells. We test these interventions in a randomized cross-over trial in IPF patients.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 12 participants
Intervention Model: Single Group Assignment
Intervention Model Description: Participants will receive sildenafil for three months then losartan for three months, then sildenafil and losartan for three months and then placebo for three months in a random order.
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Clinical Treatment Trial Targeting Vascular Reactivity in Idiopathic Pulmonary Fibrosis
Actual Study Start Date : September 2009
Actual Primary Completion Date : December 2016
Actual Study Completion Date : December 2016


Arm Intervention/treatment
Experimental: All study participants
Study participants are patients that have been diagnosed with idiopathic pulmonary fibrosis (IPF).
Drug: Sildenafil
Sildenafil 20mg three times per day for 3 months followed by a one month washout prior to next intervention.
Other Names:
  • Viagra
  • Revatio

Drug: Losartan
Losartan 25mg two times a day for 3 months followed by a one month washout prior to next intervention.
Other Name: Cozaar: losartan

Drug: Sildenafil and Losartan
Sildenafil 20mg three times per day and Losartan 25mg two times per day followed by a one month washout prior to next intervention.
Other Names:
  • Viagra, Revatio: sildenafil
  • Cozaar: losartan

Drug: Placebo Oral Tablet
Placebo pill three times per day for 3 months followed by a one month washout prior to next intervention.
Other Name: Placebo pill (sugar)




Primary Outcome Measures :
  1. Change in Six Minute Walk Distance in Meters [ Time Frame: At baseline and three months post each intervention. ]
    Change in 6MWD before and after treatment compared to placebo


Secondary Outcome Measures :
  1. Change in Forced Vital Capacity (FVC) [ Time Frame: At baseline and three months post each intervention. ]
    Change in FVC before and after treatment compared to placebo. FVC is a measure of lung size.

  2. Change in Shortness of Breath (SOB) Score [ Time Frame: At baseline and three months post each intervention. ]
    Change in symptoms of SOB as determined by St. Georges Respiratory Questionnaire score. This score ranges from 0 to 100 with a higher score indicating more problems breathing.



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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age 18-99
  • Have not taken any of the study medications in the past 6 weeks
  • Diagnosed with idiopathic pulmonary fibrosis

Exclusion Criteria:

  • FVC<50%, DLco <30% or FEV1/FVC ratio <65%
  • Greater amount of emphysema than fibrotic change on chest CT scan
  • Acute myocardial infarction within the past 6 months
  • Nitrate use
  • Contraindications, hypersensitivity, or allergic reaction to any study medication
  • Presence of aortic stenosis
  • Life-threatening arrhythmia within 1 month of evaluation
  • Diabetes requiring insulin therapy
  • Second-degree or third-degree atrioventricular block on electrocardiogram
  • Echocardiographic evidence of severe pulmonary hypertension (>50mmHg) • Severe terminal illness (survival predicted to be less than 1 year)
  • Severe congestive heart failure
  • Renal impairment (creatinine >2.0 mg/dl)
  • Moderate to severe hepatic impairment
  • Concurrent treatment with immunosuppressive, cytotoxic, or investigational agents.
  • Pregnant or Breastfeeding (Women of childbearing age must use effective form of birth control or abstinence during study participation)
  • History of acute exacerbation of IPF
  • Current enrollment in another investigational protocol
  • Acute or chronic impairment other than dyspnea that limits the patient's ability to perform the six minute walk test
  • Current drug or alcohol dependence
  • Initiation of pulmonary rehabilitation within 30 days of enrollment. Subjects currently undergoing maintenance pulmonary rehabilitation at study entry will be asked to maintain their levels of rehabilitation for the duration of the trial
  • Treatment of pulmonary hypertension with prostaglandins, endothelin-1 antagonists, or any other phosphodiesterase inhibitor within 30 days of enrollment
  • Addition or discontinuation of calcium channel blockers, digitalis, diuretics or vasodilators within 30 days of enrollment. Dosage must be stable for 7 days prior to enrollment (except for diuretics)
  • Listed for lung transplantation
  • Due to drug interactions, all of the following agents will be prohibited: alpha-blockers, endothelin-1 antagonists, and CYP3A4 inhibitors
  • Resting oxygen saturation of <92% with greater than 6 liters of supplemental oxygen

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00981747


Locations
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United States, Iowa
University of Iowa Hospitals and Clinics
Iowa City, Iowa, United States, 52246
Sponsors and Collaborators
Alicia Gerke
Pulmonary Fibrosis Foundation
Investigators
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Principal Investigator: Alicia K Gerke, MD University of Iowa

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Responsible Party: Alicia Gerke, Assistant Professor, University of Iowa
ClinicalTrials.gov Identifier: NCT00981747     History of Changes
Other Study ID Numbers: 200906736
First Posted: September 22, 2009    Key Record Dates
Results First Posted: November 12, 2018
Last Update Posted: November 12, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:
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Fibrosis
Pulmonary Fibrosis
Idiopathic Pulmonary Fibrosis
Idiopathic Interstitial Pneumonias
Pathologic Processes
Lung Diseases
Respiratory Tract Diseases
Lung Diseases, Interstitial
Sildenafil Citrate
Losartan
Vasodilator Agents
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Urological Agents
Anti-Arrhythmia Agents
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists