The Short Term Safety and Efficacy of Inhaled L-arginine in Patients With Cystic Fibrosis

Study Overview
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Brief Summary
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The objective of this trial is to determine the safety and effect on pulmonary function of 14 days of inhaled L-arginine versus placebo administered over a period of 14 days in a cohort of CF patients.

Detailed Description
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Despite the inflammatory nature of lung disease in CF, nitric oxide (NO) formation as well as the expression of NOS2 has been found to be decreased in CF airways. While the reasons for impaired airway NO formation remain incompletely understood, there is evidence that low NO formation contributes to lung pathophysiology in CF. Constitutive endogenous formation of Nitric oxide (NO) in airways is thought to play a role in neurotransmission, smooth muscle relaxation and bronchodilation. Previous animal experiments have shown that the addition of L-arginine, the precursor of enzymatic NO formation, resulted in a significantly greater relaxation of tracheas. There is also evidence that a single dose of inhaled L-arginine improves pulmonary function in CF. In this study we will assess the effect of L-arginine inhalation on lung function, nitric oxide formation, airway inflammation and bacterial infection in CF patients.

Official Title
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Pilot Study of the Short Term Safety and Efficacy of Inhaled L-arginine in Patients With Cystic Fibrosis

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: L-arginine
* Drug: L-arginine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of CF as defined by two or more clinical features of CF and a documented sweat chloride concentration > 60 mEq/L and/or two well characterized disease causing CFTR gene mutations 14 years of age and older at enrollment Clinically stable at enrollment Ability to comply with medication use, study visits and study procedures FEV1 % predicted > 40% < 80 % as calculated by reference equations Exclusion Criteria: Respiratory culture positive for: B. cepacia complex within past year or at screening Use of systemic corticosteroids within 30 days of screening Use of intravenous antibiotics or oral quinolones within 14 days of screening History of biliary cirrhosis, portal hypertension, or splenomegaly Other major organ dysfunction History of lung transplantation or currently on lung transplant list Supplemental oxygen therapy Oxygen saturation < 95 % on room air Positive pregnancy test at screening Investigational drug use within 30 days of screening History of alcohol, illicit drug or medication abuse within 1 year of screening Acute respiratory symptoms Inability to take any form of bronchodilator Wheezing at the time of study

Ages Eligible for Study
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Minimum Age: 14 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: L-arginine<br>* Group 1 will receive the active treatment followed by the inactive treatment. The active treatment phase will consist of L-arginine 250 mg/ml dispensed in 2.2 ml vials, from which the patient will take 2ml (500mg) and dilute with 3ml of sterile water to give 5ml of a 100mg/ml solution. Dosing in the inactive treatment phase will consist of a placebo of similar osmolarity and appearance will be formulated and dosed in a similar fashion. It will consist of 2.2ml vials of 1110mmol/L hypertonic saline. Again, the patient will take 2ml and dilute with 3ml of sterile water to give a 445mmol/L solution which has similar tonicity (10%) to the L-arginine. Both treatment phases will be administered by inhalation with a PARI eFLOW device.<br>|
| Experimental: 2<br> | Drug: L-arginine<br>* Group 2 will receive the inactive treatment followed by the active treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in FEV1 (in liters) from baseline |  | At the end of the 14 day treatment period | 
| Adverse events such as gastrointestinal complaints, wheezing, hepatitis or shortness of breath |  | 70 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in FVC and change in FEV25-75 from baseline to completion of the 2 week treatment period. |  | Will be measured at the end of the 14 day treatment period | 
| Change in exhaled nitric oxide (FeNO) |  | 70 days | 
| Changes in inflammatory markers in sputum from baseline including neutrophils (sputum), neutrophil elastase (sputum) and interleukin (IL)-8 concentrations (sputum). |  | Will me measured at the end of the 14 day treatment period | 
| Changes in sputum concentrations of L-arginine metabolites |  | 70 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cystic Fibrosis, L-Arginine, Pediatrics, pulmonary function