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

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ClinicalTrials.gov Identifier: NCT02433977
Recruitment Status : Recruiting
First Posted : May 5, 2015
Last Update Posted : December 19, 2018
Sponsor:
Information provided by (Responsible Party):
Sally E. Wenzel MD, University of Pittsburgh

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Asthma Dietary Supplement: Conjugated Linolenic Acid Drug: Sodium Nitrite Drug: Sodium Nitrate Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Proof of Concept Study to Determine the Effects of NOX and Conjugated Linoleic Acid on Asthmatics
Actual Study Start Date : September 2015
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : May 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Asthma

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 Name: 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)




Primary Outcome Measures :
  1. Change in exhaled NO before and after treatment [ Time Frame: 8 weeks ]
    Determine how CLA and NOx affect airway NO bioavailability (exhaled NO)


Secondary Outcome Measures :
  1. Biomarkers of Inflammation-bronchial hyperresponsiveness [ Time Frame: 8 weeks ]
    To determine whether, compared to baseline, treatment with NOx + CLA can reduce bronchial hyperresponsiveness

  2. Biomarkers of Inflammation- concentration of nitrite/nitrate, free CLA and NO2-CLA [ Time Frame: 8 weeks ]
    To determine whether, compared to baseline, treatment with NOx + CLA can quantify the concentrations of nitrate/nitrite in plasma and urine, free cLA in plasma, and NO2-cLA in BALF, plasma, and urine

  3. Biomarkers of Inflammation-airway oxidation and inflammation [ Time Frame: 8 weeks ]
    To determine whether, compared to baseline, treatment with NOx + CLA can reduce airway oxidation and inflammation

  4. Biomarkers of Inflammation-airway XO activity [ Time Frame: 8 weeks ]
    To determine whether, compared to baseline, treatment with NOx + CLA can effect airway XO activity determined in endobronchial biopsies

  5. Biomarkers of Inflammation-15NO2-cLA and endogenous 14NO2-cLA [ Time Frame: 8 weeks ]
    To determine whether, compared to baseline, treatment with NOx + CLA can effect measurement of 15NO2-cLA and endogenous 14NO2-cLA in urine, plasma and BAL

  6. Biomarkers of Inflammation-anion superoxide [ Time Frame: 8 weeks ]
    To determine whether, compared to baseline, treatment with NOx + CLA can decrease production of anion superoxide in fresh airway epithelial cells

  7. Biomarkers of Inflammation-mitochondrial ROS production and bioenergetics [ Time Frame: 8 weeks ]
    To determine whether, compared to baseline, treatment with NOx + CLA can effect mitochondrial ROS production and bioenergetics in fresh and cultured airway epithelial cells.



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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02433977


Contacts
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Contact: Sally E Wenzel, MD 4126479955 swenzel@pitt.edu
Contact: Melissa Ilnicki, RRT RPSGT 412-864-0865 ilnickima@upmc.edu

Locations
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United States, Pennsylvania
The University of Pittsburgh Asthma Institute at UPMC Recruiting
Pittsburgh, Pennsylvania, United States, 15213
Contact: Sally Wenzel, MD    412-647-9955    swenzel@pitt.edu   
Contact: Melissa Ilnicki, RRT RPSGT    412-864-0865    ilnickima@upmc.edu   
Sponsors and Collaborators
Gladwin, Mark, MD
Investigators
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Principal Investigator: Sally E Wenzel, MD The University of Pittsburgh Asthma Institute at UPMC

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Responsible Party: Sally E. Wenzel MD, Professor of Medicine, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT02433977     History of Changes
Other Study ID Numbers: PRO14110207
First Posted: May 5, 2015    Key Record Dates
Last Update Posted: December 19, 2018
Last Verified: December 2018
Keywords provided by Sally E. Wenzel MD, University of Pittsburgh:
Asthma
Obesity
conjugated linolenic acid
nitrate
nitrite
nutritional supplements
Additional relevant MeSH terms:
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Asthma
Bronchial Diseases
Respiratory Tract Diseases
Lung Diseases, Obstructive
Lung Diseases
Respiratory Hypersensitivity
Hypersensitivity, Immediate
Hypersensitivity
Immune System Diseases