Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

Effect of Simvastatin on CF Airway Inflammation

This study has been completed.
Sponsor:
Collaborator:
Cystic Fibrosis Foundation
Information provided by:
Akron Children's Hospital
ClinicalTrials.gov Identifier:
NCT00255242
First received: November 16, 2005
Last updated: July 31, 2009
Last verified: January 2008
  Purpose

Individuals with cystic fibrosis (CF) have persistent infection in the airways, which the body attempts to fight by recruiting immune cells (neutrophils) to the lung. The immune system and neutrophils are unable to completely kill the bacteria, and the response to the infection leads to inflammation (swelling) of the airways and lung damage. Nitric oxide (NO) has anti-bacterial and anti-inflammatory properties in the lung. NO production is decreased in CF patients, and may contribute to the persistent infection and inflammation. Increasing the production of NO in the airways of CF patients may help decrease this inflammation and infection.

Rho GTPases are molecules in the cells that line the airways that decrease the protein that makes nitric oxide (NOS). Rho proteins also increase inflammation in these cells. Rho proteins are increased in CF cells, and may partially explain the low NO and high inflammation seen in CF. Blocking the Rho protein in CF cells increases NOS, which can then produce more NO. The Rho protein can be inhibited with a drug, simvastatin (Zocor®). Simvastatin is used by millions of people to lower their cholesterol, is very safe, has few side-effects and is approved for use in children greater than 10 years of age. We propose that treating CF patients with simvastatin will increase NO produced (exhaled NO), and may decrease airway inflammation.

If simvastatin has these expected effects in CF, it would be another drug that has potential to become a new therapy to fight the debilitating lung damage of the disease.


Condition Intervention Phase
Cystic Fibrosis
Drug: Simvastatin treatment for 28 days
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Effect of Simvastatin on CF Airway Inflammation

Resource links provided by NLM:


Further study details as provided by Akron Children's Hospital:

Primary Outcome Measures:
  • Specific Aim 1: To determine the effect of simvastatin treatment on exhaled NO, eNO measurements from the Run-in phase will be compared to the Treatment phase. [ Time Frame: 1 month ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Specific Aim 2: Synthesis of the following markers will be measured in nasal epithelial samples by quantitative PCR. [ Time Frame: 1 months ] [ Designated as safety issue: Yes ]
  • Specific Aim 3: Cell and differential counts will be obtained in induced sputum as an overall measure of the inflammatory response.Concentrations of neutrophil products (elastase) and cytokines also will be measured in induced sputum. [ Time Frame: 1 months ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 40
Study Start Date: July 2004
Study Completion Date: May 2009
Primary Completion Date: March 2008 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Simvastatin treatment for 28 days
    40 mg / day
Detailed Description:

Cystic Fibrosis (CF) lung disease is characterized by chronic bacterial infection and excessive inflammation. The airways of patients with CF contain large amounts of neutrophils, neutrophil products, and pro-inflammatory mediators. This inflammatory response may be linked to the loss of CFTR function. It is unknown, however, what signaling mechanisms link a loss of CFTR function to the excessive inflammatory response. Several signaling pathways are dysregulated in CF epithelial cells. Among these is the pathway that leads to the production of nitric oxide (NO). Reduced production of NO, which has important antibacterial and anti-inflammatory effects in the airway, may contribute to the establishment of the chronic bacterial infection and the development of the subsequent overzealous inflammatory response in CF.

NO synthesis in the airway epithelium is regulated by nitric oxide synthase 2 (NOS2). NOS2 expression is negatively regulated by the Rho GTPases, which are over-expressed in CF and may also play a role in the inflammatory dysregulation characteristic of the lung disease. Inhibition of the Rho GTPases with 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoAR) inhibitors, such as simvastatin (Zocor®), increases NOS2 protein expression in CF airway epithelial cells. The statins have also been shown to have potent systemic anti-inflammatory effects, many of which may be pertinent to CF. We propose to test the hypothesis that HMG-CoAR inhibitors, such as simvastatin, have the potential to correct abnormalities in NO production and decrease inflammation in the airways of patients with CF. The following specific aims will be pursued in this application: 1) To determine the effect of simvastatin treatment on exhaled nitric oxide (eNO) concentrations in subjects with CF; 2) To determine the effect of simvastatin treatment on inflammation and NOS2 production in the airway of subjects with CF, as determined by quantitative RT-PCR for IL-6, IL-8, and NOS2 mRNA in nasal epithelial cells; 3) To determine if quantitative RT-PCR measurements on nasal epithelial cells might be used as a surrogate marker of lower airway inflammation by comparing the measures obtained from nasal epithelial scrapes with inflammatory measurements obtained from induced sputum.

This study has the potential to identify a new agent that targets a signaling pathway (Rho GTPase) that appears to be dysregulated in CF, and thus, may exert multiple beneficial effects in the CF airway including increasing airway NO concentrations, decreasing neutrophil influx and reducing production of inflammatory mediators. In addition to evaluating the anti-inflammatory effects of statins in CF, this study presents an opportunity to evaluate alternative outcome measures of CF airway inflammation. The results of this study will provide important information regarding the feasibility of using nasal epithelial sampling as a relatively non-invasive measure of airway inflammation in CF.

  Eligibility

Ages Eligible for Study:   10 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Cystic Fibrosis
  • > 9 yrs of age
  • Clinically stable
  • FEV1 > 50% predicted

Exclusion Criteria:

  • Hepatic disease
  • B. cepacia
  • corticosteroids
  • symptomatic allergic rhinitis
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00255242

Locations
United States, Ohio
Akron Children's Hospital
Akron, Ohio, United States, 44308
Sponsors and Collaborators
Akron Children's Hospital
Cystic Fibrosis Foundation
Investigators
Principal Investigator: Nathan C Kraynack, MD Akron Children's Hospital
  More Information

No publications provided

Responsible Party: Nathan Kraynack, MD, Akron Children's Hospital
ClinicalTrials.gov Identifier: NCT00255242     History of Changes
Other Study ID Numbers: KRAYNA04A0, KRAYNA04A0
Study First Received: November 16, 2005
Last Updated: July 31, 2009
Health Authority: United States: Institutional Review Board

Keywords provided by Akron Children's Hospital:
Cystic Fibrosis
Airway Inflammation
Cytokines
Simvastatin
HMG-CoA reductase inhibitors
Rho GTP-ase

Additional relevant MeSH terms:
Cystic Fibrosis
Fibrosis
Inflammation
Digestive System Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases
Lung Diseases
Pancreatic Diseases
Pathologic Processes
Respiratory Tract Diseases
Simvastatin
Anticholesteremic Agents
Antimetabolites
Enzyme Inhibitors
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Hypolipidemic Agents
Lipid Regulating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on November 23, 2014