AsthmaPhase 2NICLANCT02433977
The Effects of NOx and Conjugated Linoleic Acid on Asthmatics
A Phase 2 study testing Conjugated Linolenic Acid, Sodium Nitrite and Sodium Nitrate in people with Asthma, run by Gladwin, Mark, MD at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Asthma
- What is being tested?
- Conjugated Linolenic Acid, Sodium Nitrite and Sodium Nitrate
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 6 participants
- Where
- 1 siteUnited States
- Study dates
- Sep 2015to Nov 2019
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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)
Show all 23Show fewer
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
The University of Pittsburgh Asthma Institute at UPMC
Pittsburgh, Pennsylvania, 15213
About this study
Official title: 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.
Read the 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.
- Conditions
- Asthma
- Being tested
- Conjugated Linolenic Acid, Sodium Nitrite, Sodium Nitrate
- Keywords
- Asthma, Obesity, conjugated linolenic acid, nitrate, nitrite, nutritional supplements
- Medical subject headings
- Asthma, Obesity
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Conjugated Linolenic AcidDietary supplement
Also called conjugated linolenic acid (CLA)
CLA is a polyunsaturated fatty acid Subjects will receive capsules for daily oral administration at the dose of 3 g/day
Sodium NitriteDrug
Subjects will receive capsules for daily oral administration at the dose of 20 mg (2 x 10 mg)
Sodium NitrateDrug
Subjects will receive capsules for daily oral administration at the dose of 1g (2 x 500 mg)
| Study group | Role | What they receive |
|---|---|---|
| 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) Receives: Dietary Supplement: Conjugated Linolenic Acid; Drug: Sodium Nitrite; Drug: Sodium Nitrate |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Exhaled NO Before and After Treatment
Determine how CLA and NOx affect airway NO bioavailability (exhaled NO)
Measured: Before treatment at baseline and after treatment at 8 weeks
Secondary outcomes (9)
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
Measured: 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
Measured: 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.
Measured: 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
Measured: 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.
Measured: 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
Measured: 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.
Measured: 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
Measured: 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
Measured: Before treatment at baseline and after treatment at 8 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 May 2015 (estimated)
- Study startSep 2015
- Primary completionNov 2019
- Study completionNov 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for AsthmaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 6 participants (actual)
Sponsor and investigators
- Lead sponsor
- Gladwin, Mark, MD
- Responsible party
- Principal investigator, Sally E. Wenzel MD, University of Pittsburgh
- Investigators
- Sally E Wenzel, MD, Principal investigator, The University of Pittsburgh Asthma Institute at UPMC
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02433977
- Sponsor's protocol ID
- PRO14110207
- Acronym
- NICLA
- Status last verified
- Apr 2021
- First submitted
- 11 Dec 2014
- Last updated
- 27 Apr 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 27 Apr 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Proof of Concept Study to Determine the Effects of NOX and Conjugated Linoleic Acid on Asthmatics
- ClinicalTrials.gov ID
- NCT02433977
- Acronym / sponsor ID
- NICLA / PRO14110207
- Conditions
- Asthma
- Keywords
- Asthma, Obesity, conjugated linolenic acid, nitrate, nitrite, nutritional supplements
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 6 participants (actual)
- Lead sponsor
- Gladwin, Mark, MD
- Study start
- Sep 2015 (actual)
- Primary completion
- Nov 2019 (actual)
- Study completion
- Nov 2019 (actual)
- First posted
- 5 May 2015 (estimated)
- Results
- Posted 26 Mar 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Conjugated Linolenic Acid + NOx | Experimental | Dietary Supplement: Conjugated Linolenic Acid, Drug: Sodium Nitrite, Drug: Sodium NitrateThis 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) |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- 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
Key exclusion criteria (23 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Conjugated Linolenic AcidAlso: conjugated linolenic acid (CLA)CLA is a polyunsaturated fatty acid Subjects will receive capsules for daily oral administration at the dose of 3 g/day | Dietary supplement | Conjugated Linolenic Acid + NOx |
| Sodium NitriteSubjects will receive capsules for daily oral administration at the dose of 20 mg (2 x 10 mg) | Drug | Conjugated Linolenic Acid + NOx |
| Sodium NitrateSubjects will receive capsules for daily oral administration at the dose of 1g (2 x 500 mg) | Drug | Conjugated Linolenic Acid + NOx |
Primary outcome
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)
9 secondary outcomes
Biomarkers of Inflammation-bronchial Hyperresponsiveness Using PC20
Time frame: 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
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
Biomarkers of Inflammation-airway XO Activity
Time frame: 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
Biomarkers of Inflammation-anion Superoxide
Time frame: 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
Biomarkers of Inflammation- Concentration of NO2-CLA in Plasma
Time frame: 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
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Apr 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Sally E Wenzel, MD principal investigator
The University of Pittsburgh Asthma Institute at UPMC
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Conjugated Linolenic Acid, Sodium Nitrite and Sodium Nitrate in people with Asthma, run by Gladwin, Mark, MD at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 27 Apr 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 26 Mar 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Exhaled NO Before and After Treatment (time frame: Before treatment at baseline and after treatment at 8 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Apr 2021.