The Effects of NOx and Conjugated Linoleic Acid on Asthmatics

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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02433977

Acronym

NICLA

Enrollment

Registered

2015-05-05

Start date

2015-09-30

Completion date

2019-11-30

Last updated

2021-04-27

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Asthma

Keywords

Asthma, Obesity, conjugated linolenic acid, nitrate, nitrite, nutritional supplements

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.

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.

Interventions

DIETARY_SUPPLEMENTConjugated Linolenic Acid

CLA is a polyunsaturated fatty acid Subjects will receive capsules for daily oral administration at the dose of 3 g/day

DRUGSodium Nitrite

Subjects will receive capsules for daily oral administration at the dose of 20 mg (2 x 10 mg)

DRUGSodium Nitrate

Subjects will receive capsules for daily oral administration at the dose of 1g (2 x 500 mg)

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 65 Years

Healthy volunteers

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.

Design outcomes

Primary

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

Secondary

Measure	Time frame	Description
Biomarkers of Inflammation- Concentration of Free CLA in Plasma	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
Number of Participants With an Increase in IL-6 and IL-1b Expression	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.
Biomarkers of Inflammation-airway XO Activity	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
Biomarkers of Inflammation-15NO2-cLA	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.
Biomarkers of Inflammation-bronchial Hyperresponsiveness Using PC20	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
Number of Participants With a Decrease of Inflammation Using Mitochondrial ROS Production	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.
Biomarkers of Inflammation- Concentration of NO2-CLA in Plasma	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
Biomarkers of Inflammation- Concentration of NO2-CLA in Urine	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
Biomarkers of Inflammation-anion Superoxide	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

Countries

United States

Participant flow

Participants by arm

Arm	Count
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) Conjugated Linolenic Acid: CLA is a polyunsaturated fatty acid Subjects will receive capsules for daily oral administration at the dose of 3 g/day Sodium Nitrite: Subjects will receive capsules for daily oral administration at the dose of 20 mg (2 x 10 mg) Sodium Nitrate: Subjects will receive capsules for daily oral administration at the dose of 1g (2 x 500 mg)	6
Total	6

Arm

Count

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

Total

Baseline characteristics

Characteristic	Conjugated Linolenic Acid + NOx
Age, Categorical <=18 years	0 Participants
Age, Categorical >=65 years	0 Participants
Age, Categorical Between 18 and 65 years	6 Participants
Age, Continuous	40.5 years STANDARD_DEVIATION 10.3
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	6 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	0 Participants
Race (NIH/OMB) Black or African American	2 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) White	4 Participants
Region of Enrollment United States	6 participants
Sex: Female, Male Female	4 Participants
Sex: Female, Male Male	2 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	0 / 6
other Total, other adverse events	6 / 6
serious Total, serious adverse events	0 / 6