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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.
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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Conjugated Linolenic Acid + NOx | Experimental | 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) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Conjugated Linolenic Acid | Dietary Supplement | CLA is a polyunsaturated fatty acid Subjects will receive capsules for daily oral administration at the dose of 3 g/day |
|
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Sally E Wenzel, MD | The University of Pittsburgh Asthma Institute at UPMC | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The University of Pittsburgh Asthma Institute at UPMC | Pittsburgh | Pennsylvania | 15213 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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) |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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) |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change in Exhaled NO Before and After Treatment | Determine how CLA and NOx affect airway NO bioavailability (exhaled NO) | Posted | Mean | Standard Deviation | parts per billion | Before treatment at baseline and after treatment at 8 weeks |
|
Before treatment at baseline through completion of treatment at 8 weeks
The occurrence of adverse events was routinely determined through regular investigator/research coordinator assessment.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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) |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Headache | General disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Stacy Gelhaus Wendell | University of Pittsburgh | 412-648-1351 | gstacy@pitt.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Dec 11, 2018 | Jan 7, 2021 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D001249 | Asthma |
| D009765 | Obesity |
| ID | Term |
|---|---|
| D001982 | Bronchial Diseases |
| D012140 | Respiratory Tract Diseases |
| D008173 | Lung Diseases, Obstructive |
| D008171 | Lung Diseases |
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| ID | Term |
|---|---|
| C004934 | eleostearic acid |
| D012977 | Sodium Nitrite |
| C031618 | sodium nitrate |
| ID | Term |
|---|---|
| D009573 | Nitrites |
| D009608 | Nitrous Acid |
| D017672 | Nitrogen Compounds |
| D007287 | Inorganic Chemicals |
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|
| Sodium Nitrite | Drug | Subjects will receive capsules for daily oral administration at the dose of 20 mg (2 x 10 mg) |
|
| Sodium Nitrate | Drug | Subjects will receive capsules for daily oral administration at the dose of 1g (2 x 500 mg) |
|
| 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 |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
|
|
|
| Secondary | 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 | Posted | Mean | Standard Deviation | mg/mL | Before treatment at baseline and after treatment at 8 weeks |
|
|
|
|
| Secondary | 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 | Posted | Mean | Standard Deviation | Nanomolar | Before treatment at baseline and after treatment at 8 weeks |
|
|
|
|
| Secondary | 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. | Posted | Count of Participants | Participants | Before treatment at baseline and after treatment at 8 weeks |
|
|
|
|
| Secondary | 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 | Data were not collected for this Outcome Measure. The proposed aims could not be addressed with scientific rigor since the number of subjects who completed the study was very low. | Posted | Before treatment at baseline and after treatment at 8 weeks |
|
|
| Secondary | Biomarkers of Inflammation-15NO2-cLA | To determine whether, compared to baseline, treatment with NOx + CLA can effect measurement of 15NO2-cLA in urine. | Posted | Mean | Standard Deviation | nmoles/mg creatinine | Before treatment at baseline and after treatment at 8 weeks |
|
|
|
|
| Secondary | 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 | Data were not collected for this Outcome Measure. The proposed aims could not be addressed with scientific rigor since the number of subjects who completed the study was very low. | Posted | Before treatment at baseline and after treatment at 8 weeks |
|
|
| Secondary | 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. | Posted | Count of Participants | Participants | Before treatment at baseline and after treatment at 8 weeks |
|
|
|
|
| Secondary | 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 | Posted | Mean | Standard Deviation | Nanomolar | Before treatment at baseline and after treatment at 8 weeks |
|
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| Secondary | 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 | Posted | Mean | Standard Deviation | nmoles/mg creatinine | Before treatment at baseline and after treatment at 8 weeks |
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| 0 |
| 6 |
| 0 |
| 6 |
| 6 |
| 6 |
| Nausea | Gastrointestinal disorders | Systematic Assessment |
|
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| D012130 |
| Respiratory Hypersensitivity |
| D006969 | Hypersensitivity, Immediate |
| D006967 | Hypersensitivity |
| D007154 | Immune System Diseases |
| D050177 | Overweight |
| D044343 | Overnutrition |
| D009748 | Nutrition Disorders |
| D009750 | Nutritional and Metabolic Diseases |
| D001835 | Body Weight |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D017670 |
| Sodium Compounds |