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

April 5, 2021 updated by: Sally E. Wenzel MD, Gladwin, Mark, MD

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

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
6

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Change in Exhaled NO Before and After Treatment
Time Frame: Before treatment at baseline and after treatment at 8 weeks
Determine how CLA and NOx affect airway NO bioavailability (exhaled NO)
Before treatment at baseline and after treatment at 8 weeks

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Biomarkers of Inflammation-bronchial Hyperresponsiveness Using PC20
Time Frame: Before treatment at baseline and after treatment at 8 weeks
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
Time Frame: Before treatment at baseline and after treatment at 8 weeks
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
Time Frame: Before treatment at baseline and after treatment at 8 weeks
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
Time Frame: Before treatment at baseline and after treatment at 8 weeks
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
Time Frame: Before treatment at baseline and after treatment at 8 weeks
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
Time Frame: Before treatment at baseline and after treatment at 8 weeks
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
Time Frame: Before treatment at baseline and after treatment at 8 weeks
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
Time Frame: Before treatment at baseline and after treatment at 8 weeks
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
Time Frame: Before treatment at baseline and after treatment at 8 weeks
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

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Gladwin, Mark, MD

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Sally E Wenzel, MD, The University of Pittsburgh Asthma Institute at UPMC

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
September 1, 2015

Primary Completion (ACTUAL)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
November 1, 2019

Study Completion (ACTUAL)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
November 1, 2019

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
December 11, 2014

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 29, 2015

First Posted (ESTIMATE)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
May 5, 2015

Study Record Updates

Last Update Posted (ACTUAL)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
April 27, 2021

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 5, 2021

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
April 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • PRO14110207

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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