Inhaled Sodium Nitrite as an Antimicrobial for Cystic Fibrosis

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: sodium nitrite

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 35
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Children's Hospital of Pittsburgh
    • Pittsburgh, Pennsylvania, United States, 15213
      • Comprehensive Lung Center - Falk Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: sodium nitrite; Inhalation of 46 or 80 mg of sodium nitrite twice daily for four weeks	Drug: sodium nitrite; inhalation of 46 or 80 mg of sodium nitrite by electronic nebulization; Other Names: AIR001

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Schmidhofer, Mark, MD
• Collaborators: Cystic Fibrosis Foundation; Mast Therapeutics, Inc.
• Investigators: Principal Investigator: Joseph Pilewski, MD, University of Pittsburgh

Publications and helpful links

General Publications

• Major TA, Panmanee W, Mortensen JE, Gray LD, Hoglen N, Hassett DJ. Sodium nitrite-mediated killing of the major cystic fibrosis pathogens Pseudomonas aeruginosa, Staphylococcus aureus, and Burkholderia cepacia under anaerobic planktonic and biofilm conditions. Antimicrob Agents Chemother. 2010 Nov;54(11):4671-7. doi: 10.1128/AAC.00379-10. Epub 2010 Aug 9.
• Zemke AC, Shiva S, Burns JL, Moskowitz SM, Pilewski JM, Gladwin MT, Bomberger JM. Nitrite modulates bacterial antibiotic susceptibility and biofilm formation in association with airway epithelial cells. Free Radic Biol Med. 2014 Dec;77:307-16. doi: 10.1016/j.freeradbiomed.2014.08.011. Epub 2014 Sep 16.

Study record dates

Study Major Dates

• Study Start: February 1, 2016
• Primary Completion (Anticipated): December 1, 2022
• Study Completion (Anticipated): April 1, 2023

Study Registration Dates

• First Submitted: January 11, 2016
• First Submitted That Met QC Criteria: February 23, 2016
• First Posted (Estimate): February 29, 2016

Study Record Updates

• Last Update Posted (Actual): July 11, 2022
• Last Update Submitted That Met QC Criteria: July 7, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis
• Other Study ID Numbers: PRO15040062

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No