Inhaled Sodium Nitrite as an Antimicrobial for Cystic Fibrosis

Study Overview
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Brief Summary
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This study will assess the safety of inhaled sodium nitrite in adults with Cystic Fibrosis and chronic Pseudomonas infections, and determine the ability of sodium nitrite to reduce the burden of Pseudomonas.

Detailed Description
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Pseudomonas aeruginosa infects the airways of 80% of adults with Cystic Fibrosis (CF). In these patients, P. aeruginosa forms extremely antibiotic resistant biofilm communities that accelerate progression of obstructive lung disease. Current treatment of airway infection focuses on monthly cycles of inhaled antibiotics. However up to 20% of adults are infected with multi drug resistant P. aeruginosa for which we have no effective inhaled treatments. These isolates are more common as patients age so with the increasing life expectancy of the CF population, MDR P. aeruginosa is likely to remain a clinical problem. Another 10% of patients are infected with other Gram-negative organisms such as Burkholderia cepacia and Achromobacter species, for which we have inadequate suppressive treatment. Following lung transplant, MDR airway infections remain a problem as the allografts are colonized by strains carried in the paranasal sinuses. Sodium nitrite may present a new antimicrobial approach to treating respiratory infection with Gram-negative organisms, because it is able to prevent biotic biofilm formation. Within the CF lung, P. aeruginosa grows as a biotic biofilm in association with airway epithelial cells and mucous plaques. This environment has an acidic pH and low oxygen tension with many bacteria subsisting through denitrification (both conditions where traditional antibiotics are less effective). Because biotic biofilms can be up to 500-fold more resistant than biofilms grown on abiotic surfaces, with support from our CF Research Development Program (RDP) Cores, we showed that nitrite prevents biofilm formation on the surface of primary CF airway epithelial cells. Moreover, nitrite dose-dependently potentiates the effects of colistin sulfate in liquid culture, and in biotic biofilms on airway epithelial cells. These data support the hypothesis that nebulized sodium nitrite will inhibit growth of Pseudomonas aeruginosa in CF airways, and identify a potential therapeutic benefit for nitrite alone and cooperatively with colistin as a novel therapy to inhibit P. aeruginosa in CF airways. Nebulized nitrite has been through extensive animal toxicology, and is well tolerated by subjects with pulmonary arterial hypertension where it is being studied as a pulmonary vasodilator. To determine the therapeutic potential of sodium nitrite for CF, we propose two specific aims: Aim 1: Determine the safety of nebulized sodium nitrite administered in two doses to patients with CF. Aim 2: Explore the effects of inhaled sodium nitrite on measures of lung function, exhaled airway nitric oxide, and bacterial burden as measured by quantitative sputum cultures. To accomplish these aims, we propose a Phase I/II open-label study of sodium nitrite in CF. Key inclusion criteria include individuals over the age 18 with cystic fibrosis as documented by clinical features of CF, and genotyping or a positive sweat test. Exclusion criteria include advanced lung disease, inability to discontinue inhaled antibiotics for four weeks, hospitalization or medication change within 4 weeks of enrollment, baseline systemic hypotension (SBP<90 mm hg), chronic kidney disease (Cr >2.5), severe anemia (Hgb <9 gm/dL in the last six months). The primary outcome is safety, defined as FEV1 measured before and after initial doses on days 0 and 7, and at week 4. Other safety data for the initial doses include pulse oximetry and transcutaneous methemoglobin levels. Secondary endpoints include quantitative sputum cultures, exhaled nitric oxide, sputum nitrite concentration, and patient symptoms as assessed by a CF specific respiratory questionnaire. Completion of this study will guide the development of sodium nitrite as a single agent for CF infections, and inform future studies examining the effects of sodium nitrite in combination with inhaled colistin for patients with drug resistant bacterial pathogens that are an increasing problem. In addition, the study will provide important safety and efficacy data that may inform future development of inhaled sodium nitrite as a therapy in young patients to augment airway host defense and prevent biofilm formation.

Official Title
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Phase I/II Study of Inhaled Sodium Nitrite as an Antimicrobial for Pseudomonas Infection in Cystic Fibrosis

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: sodium nitrite


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Cystic Fibrosis as documented by clinical features, and documentation of a positive sweat test or two disease causing mutation of the CF gene. Exclusion Criteria: use of supplemental oxygen, FEV1 < 40% predicted, inability to discontinue inhaled antibiotics for 4 weeks, hospitalization within 4 weeks prior to enrollment, change in maintenance CF therapies within 4 weeks of enrollment, severe anemia, significant chronic liver disease, severe pulmonary hypertension, prior organ transplantation

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: sodium nitrite<br>Inhalation of 46 or 80 mg of sodium nitrite twice daily for four weeks | Drug: sodium nitrite<br>* inhalation of 46 or 80 mg of sodium nitrite by electronic nebulization<br>* Other names: AIR001;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pulmonary Function | change in forced expiratory volume in one second (FEV1) after inhalation will assess safety | three times over 4 weeks (Day 0, Day 7, and Week 4) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| exhaled Nitric Oxide | concentration of nitric oxide in exhaled breath | three times over 4 weeks (Day 0, Day 7, and Week 4) | 
| sputum nitrite concentration | concentration of nitrite in sputum | three times over 4 weeks (Day 0, Day 7 and Week 4) | 
| Pseudomonas density in sputum | density of Pseudomonas in sputum | two times over 4 weeks (Day 0 and Week 4) | 
| CF questionnaire - Respiratory | respiratory symptom questionnaire | two times over 4 weeks (Day 0 and Week 4) |