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

Sponsor

The Hospital for Sick Children (Other)

Overall Status

Completed

CT.gov ID

NCT00405665

Collaborator

(none)

Enrollment

Locations

Arms

Duration (Months)

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Cystic Fibrosis	Drug: L-arginine Drug: L-arginine	Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

20 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Nov 1, 2006

Actual Primary Completion Date :

Jun 1, 2009

Actual Study Completion Date :

Jun 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1	Drug: L-arginine 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.
Experimental: 2	Drug: L-arginine Group 2 will receive the inactive treatment followed by the active treatment.

Arm

Intervention/Treatment

Experimental: 1

Drug: L-arginine

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.

Experimental: 2

Drug: L-arginine

Group 2 will receive the inactive treatment followed by the active treatment.

Outcome Measures

Primary Outcome Measures

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

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

14 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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