The Effects of NOx and Conjugated Linoleic Acid on Asthmatics (NICLA)

A Proof of Concept Study to Determine the Effects of NOX and Conjugated Linoleic Acid on Asthmatics

This study will examine the hypothesis that in obese asthmatics; treatment with NOx + CLA is well tolerated, safe and will increase eNO while reducing airway oxidative stress. Allied with this, the investigators will define whether supplementing with this bioactive mediator modifies the airway microbiome, and reduces airway inflammation.

Study Overview

• Status: Completed
• Conditions: Asthma
• Intervention / Treatment: Dietary supplement: Conjugated Linolenic Acid; Drug: Sodium Nitrite; Drug: Sodium Nitrate

Detailed Description

Obesity is an asthma comorbidity associated with increased severity, poor control, reduced steroid responsiveness and greater exacerbation and healthcare utilization rates. These associations are not explained by having a greater degree of Th-2 inflammation. Rather, the obese asthma phenotype defined in several cluster studies, has paradoxically reduced levels of Th-2 biomarkers, including sputum eosinophils and exhaled nitric oxide (NO). The investigators previous research has shown that the inverse relation between increased body mass index (BMI) and reduced exhaled NO, may be explained by a metabolic imbalance characterized by lower L-arginine and greater asymmetric di-methyl arginine (ADMA) levels. Having a low L-arginine/ADMA ratio has been shown to inhibit and uncouple all isoforms of nitric oxidase synthase (NOS), thereby reducing NO bioavailability and promoting oxidative stress through enhanced superoxide production. In obese asthmatics, this imbalance not only correlates with exhaled NO, but also with lower FEV1% and poorer asthma-related quality of life. Yet the effect of obesity in asthma is unlikely to be solely dependent on a single mechanism. Other factors, such as increased Th1 and Th-17-mediated inflammation have been shown to occur in human and animal models. Given all of these potential avenues, it is imperative that an intervention is sufficiently pleiotropic that can, in addition to restoring airway NO levels, also reduce other obesity-related non-Th2 mechanism of inflammation. The investigators hypothesize that treatment with conjugated linolenic acid (CLA) + nitrate and nitrite (together known as NOx), will restore NO airway bioavailability, reduce oxidative stress and improve airway inflammation in obese asthmatics. To test this hypothesis, the investigators propose a phase II pilot study in which obese asthmatics with metabolic syndrome, will be treated orally with CLA+NOx for 8 weeks, in an open label study design to assess pre to post-intervention changes in airway and systemic biomarkers, and to determine the effects on lung function and bronchial hyperresponsiveness. Participants will undergo a pre and post intervention bronchoscopy. The results obtained from this project will be greatly informative to our understanding of the obese - asthma pathophysiology and for the development of clinical trials to determine the potential benefit of this intervention in improving health outcomes.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • The University of Pittsburgh Asthma Institute at UPMC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adequate completion of informed consent process with written documentation
• Male and female patients, ≥ 18 - 65 yrs old
• Diagnosis of asthma: based on previous physician diagnosis and either baseline pre-bronchodilator FEV1 50% or greater predicted with a 12% or greater bronchodilator response to 4 puffs of albuterol or PC20 methacholine (16 mg) if no BD response.If the subject is not currently on an ICS/ ICS LABA, PC20 should be < 8 mg, if no BD response. Spirometry results within the prior 24 months located in the subject's medical records can be used to determine eligibility, if available.
• All racial/ethnic backgrounds with a diagnosis of asthma for ≥6 months
• Smoking history ≤10 pack years and no smoking in the last year
• BMI ≥ 30
• If subject is on ICS or ICS/LABA therapy- 30 days on a stable dose (up to 1,000 mcg daily fluticasone equivalent)
• Asthma diagnosed at age 9 or later

Exclusion Criteria:

• Respiratory tract infection within the last 4 weeks
• Oral or systemic CS burst within the last 4 weeks
• Asthma-related hospitalization within the last 2 months
• Asthma-related ER visit within the previous 4 weeks
• Significant or uncontrolled concomitant medical illness including (but not limited to) heart disease, cancer, diabetes
• Chronic renal failure (creatinine > 2.0) at screening (Associated with higher ADMA levels)
• Current statins use (statins lower ADMA levels), patients may stop and re-enroll after 2 weeks of stopping statins
• Positive pregnancy test
• Intolerance or allergy to the intervention drugs
• Current or recent (within 30 days) in an investigational treatment study.
• Unable or unlikely to complete study assessments or the study intervention (i.e. bronchoscopy) poses undue risk to patient in the opinion of the Investigator.
• Any kind of oral nitrates such as nitroglycerin or already taking supplements
• History of ICU admission/intubation due to asthma in the past year;
• More than three systemic corticosteroid requiring asthma exacerbations in the past year
• Systemic steroid dependent asthma (no daily oral steroids- short term therapy for asthma exacerbation is permitted)
• Use of mouthwash containing chlorhexidine (lowers NO) within 1 week prior to screening and throughout the study
• Untreated sleep apnea
• Hgb A1C ≥7
• Daily use of PPI's (Proton Pump Inhibitor) or H2 Blockers for GERD (it is permitted to take on an occasional basis- no more than 1x per week. If participants wash out of these meds for 1 week, they can enroll)
• Use of biologics for asthma/allergies unless there is a 4 month washout prior to enrollment (the washout for biologics is done for clinical reasons and not specifically for inclusion for the study).
• Drug and/or alcohol abuse for ≥1 year
• Breastfeeding
• Any other condition and/or situation that causes the investigator to deem a subject unsuitable for the study (e.g. due to expected study medication non-compliance, inability to medically tolerate the study procedures, or a subject's unwillingness to comply with study-related procedures.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Conjugated Linolenic Acid + NOx; This is a single arm study Conjugated Linolenic Acid (CLA)- daily oral dose 3 g/day Sodium Nitrate- Capsules for daily oral administration at the dose of 1 g (2 x 500 mg) Sodium Nitrite- Capsules for daily oral administration at the dose of 20 mg (2 x 10 mg)

Dietary supplement: Conjugated Linolenic Acid; CLA is a polyunsaturated fatty acid Subjects will receive capsules for daily oral administration at the dose of 3 g/day; Other Names: conjugated linolenic acid (CLA); Drug: Sodium Nitrite; Subjects will receive capsules for daily oral administration at the dose of 20 mg (2 x 10 mg); Drug: Sodium Nitrate; Subjects will receive capsules for daily oral administration at the dose of 1g (2 x 500 mg)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Exhaled NO Before and After Treatment	Determine how CLA and NOx affect airway NO bioavailability (exhaled NO)	Before treatment at baseline and after treatment at 8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biomarkers of Inflammation-bronchial Hyperresponsiveness Using PC20	To determine whether, compared to baseline, treatment with NOx + CLA can reduce bronchial hyperresponsiveness. PC20 was measured by methacholine challenge (mg/mL) in three participants pre and post supplementation with Nitrate/Nitrite and cLA	Before treatment at baseline and after treatment at 8 weeks
Biomarkers of Inflammation- Concentration of Free CLA in Plasma	To determine whether, compared to baseline, treatment with NOx + CLA can quantify the concentrations of free CLA in plasma	Before treatment at baseline and after treatment at 8 weeks
Number of Participants With an Increase in IL-6 and IL-1b Expression	To determine whether, compared to baseline, treatment with NOx + CLA will increase a participant's IL-6 and IL-1b expression.	Before treatment at baseline and after treatment at 8 weeks
Biomarkers of Inflammation-airway XO Activity	To determine whether, compared to baseline, treatment with NOx + CLA can effect airway XO activity determined in endobronchial biopsies	Before treatment at baseline and after treatment at 8 weeks
Biomarkers of Inflammation-15NO2-cLA	To determine whether, compared to baseline, treatment with NOx + CLA can effect measurement of 15NO2-cLA in urine.	Before treatment at baseline and after treatment at 8 weeks
Biomarkers of Inflammation-anion Superoxide	To determine whether, compared to baseline, treatment with NOx + CLA can decrease production of anion superoxide in fresh airway epithelial cells	Before treatment at baseline and after treatment at 8 weeks
Number of Participants With a Decrease of Inflammation Using Mitochondrial ROS Production	To determine whether, compared to baseline, treatment with NOx + CLA can decrease inflammation using mitochondrial ROS production in fresh and cultured airway epithelial cells.	Before treatment at baseline and after treatment at 8 weeks
Biomarkers of Inflammation- Concentration of NO2-CLA in Plasma	To determine whether, compared to baseline, treatment with NOx + CLA can quantify the concentrations of NO2-cLA in plasma	Before treatment at baseline and after treatment at 8 weeks
Biomarkers of Inflammation- Concentration of NO2-CLA in Urine	To determine whether, compared to baseline, treatment with NOx + CLA can quantify the concentrations of NO2-cLA in urine	Before treatment at baseline and after treatment at 8 weeks

Collaborators and Investigators

• Sponsor: Gladwin, Mark, MD
• Investigators: Principal Investigator: Sally E Wenzel, MD, The University of Pittsburgh Asthma Institute at UPMC

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 1, 2015
• Primary Completion (ACTUAL): November 1, 2019
• Study Completion (ACTUAL): November 1, 2019

Study Registration Dates

• First Submitted: December 11, 2014
• First Submitted That Met QC Criteria: April 29, 2015
• First Posted (ESTIMATE): May 5, 2015

Study Record Updates

• Last Update Posted (ACTUAL): April 27, 2021
• Last Update Submitted That Met QC Criteria: April 5, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: Obesity; Asthma; nitrate; nitrite; nutritional supplements; conjugated linolenic acid
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Asthma
• Other Study ID Numbers: PRO14110207