Anti-Inflammatory Lipid Mediator for Asthma

(ALMA; LIMA Trial)

Overseen By Asthma Research

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Colorado, Denver

Must be taking: Inhaled corticosteroids, Long acting beta agonists

Disqualifiers: Recent infection, Recent steroids, Smoking, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 2

Duration: 6 weeks

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called CXA-10, an anti-inflammatory lipid mediator, which aims to reduce lung inflammation in people with asthma who are also obese. Obesity can worsen asthma by increasing inflammation, and the study will determine if CXA-10 can alleviate this. Participants will receive either CXA-10 or a placebo (a pill with no active drug), with a switch after a few weeks to compare results. Suitable candidates have had asthma for more than six months, use inhalers regularly, and have a BMI of 30 or higher. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial requires that you continue taking your regular asthma medications, such as inhaled corticosteroids, long-acting beta agonists, and long-acting muscarinic antagonists, as long as you have been on a stable dose for at least 4 weeks before starting the study.

Is there any evidence suggesting that CXA-10 is likely to be safe for humans?

Research shows that CXA-10 is being tested for its potential to reduce inflammation in people with asthma, particularly those who are overweight. Earlier studies have examined CXA-10's effects on inflammation and metabolism. Although complete details about its safety in humans are not yet available, its presence in Phase 2 trials indicates it has passed some initial safety checks.

Typically, a treatment in Phase 2 has already demonstrated likely safety in a small group of people. However, more information from the current study will clarify how well participants can tolerate it. If CXA-10 proves safe and effective, it could offer a new approach to managing asthma symptoms in overweight adults. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for asthma?

Most treatments for asthma focus on relieving symptoms by reducing inflammation or opening airways, like inhaled corticosteroids and bronchodilators. But CXA-10 works differently, targeting inflammation at a cellular level by acting as an anti-inflammatory lipid mediator. Researchers are excited about CXA-10 because it could offer a new approach to controlling asthma, potentially reducing reliance on steroids and minimizing side effects. Plus, its oral administration makes it easy to use compared to traditional inhaled medications.

What evidence suggests that CXA-10 might be an effective treatment for asthma?

Research has shown that CXA-10, a lab-made compound, may help reduce inflammation related to asthma, particularly in obese individuals. Studies have found that CXA-10 decreases inflammation throughout the body and in the airways, key factors in asthma linked to obesity. The treatment affects certain proteins involved in fat metabolism and immune responses, which can reduce airway sensitivity. Animal research also suggests that CXA-10 might aid other inflammatory conditions, supporting its use in treating asthma related to obesity. This trial will compare CXA-10 with a matching placebo to evaluate its effectiveness in managing asthma symptoms in obese adults by targeting inflammation. ^{1 6 7 8 9}

Who Is on the Research Team?

Fernando Holguin, MD, MPH

Principal Investigator

University of Colorado Denver- Anschutz Medical Campus

Are You a Good Fit for This Trial?

Adults aged 18-65 with obesity (BMI ≥30) and asthma, using regular inhaled corticosteroids or other long-term asthma medications. Women must be non-pregnant, post-menopausal, surgically sterile, or agree to use contraception. Excluded are those recently hospitalized for asthma, had a respiratory infection or steroid treatment within the last month, severe asthmatics with frequent exacerbations, or current/recent smokers.

Inclusion Criteria

Adequate completion of informed consent process with written documentation

You have a body mass index (BMI) of 30 or higher.

I have been diagnosed with asthma for over 6 months and respond to asthma medication.

Exclusion Criteria

I was hospitalized for asthma in the last 6 weeks.

I have not taken any corticosteroids in the last 4 weeks.

I have not had a respiratory infection in the last 4 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive CXA-10 or placebo orally, continuously, and daily for 6 weeks

6 weeks

1 visit (in-person) for drug dispensing

Washout

Participants undergo a washout period before crossover

4 weeks

Crossover Treatment

Participants receive the alternate treatment (CXA-10 or placebo) for an additional 6 weeks

6 weeks

1 visit (in-person) for drug dispensing

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 weeks

What Are the Treatments Tested in This Trial?

Interventions

• CXA-10

Trial Overview The trial is testing CXA-10's effectiveness against placebo in reducing inflammation in obese adults with asthma. It's a Phase 2 study where participants will receive either the synthetic nitro-fatty acid CXA-10 or a placebo without knowing which one they're getting to compare outcomes.

How Is the Trial Designed?

Group I: CXA-10 Experimental Treatment 1 Intervention

Administered orally, continuously, and daily for at least 6 weeks. Dispensed at Visit 1. Washout period of at least 4 weeks and then enter crossover phase of an additional 6 weeks. Drug will be dispensed at Visit 4.

Group II: Matching Placebo Placebo Group 1 Intervention

Administered orally, daily, and continuously for at least 6 weeks. Dispensed at Visit 1. Washout period of at least 4 weeks and then enter crossover phase of an additional 6 weeks. Placebo will be dispensed at Visit 4.

Who Is Running the Clinical Trial?

University of Colorado, Denver

Lead Sponsor

Trials

1,842

Recruited

3,028,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

Published Research Related to This Trial

CRBM-0244, a new derivative of docosahexaenoic acid (DHA), effectively prevents bronchial hyperresponsiveness and reduces inflammation in both human bronchi and a guinea pig model of allergic asthma, indicating its potential as a therapeutic agent for asthma.

The mechanism of action involves the inhibition of NF-κB activation and COX-2 overexpression, along with a reduction in Ca(2+) sensitivity of bronchial smooth muscle, suggesting that CRBM-0244 modulates inflammatory responses through specific biochemical pathways.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Docosahexaenoic acid derivative prevents inflammation and hyperreactivity in lung: implication of PKC-Potentiated inhibitory protein for heterotrimeric myosin light chain phosphatase of 17 kD in asthma. Morin, C., Fortin, S., Cantin, AM., et al.[2020]

CXA-10, a novel nitro fatty acid, has shown promise in reducing biomarkers of inflammation and metabolic stress in healthy and obese subjects, indicating its potential therapeutic effects in conditions related to oxidative stress.

The compound was found to be safe and well-tolerated, with dose-related adverse events primarily including diarrhea, abdominal pain, and nausea, and no significant clinical abnormalities reported, paving the way for ongoing Phase II studies in patients with specific diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic and Pharmacodynamic Effects of Oral CXA-10, a Nitro Fatty Acid, After Single and Multiple Ascending Doses in Healthy and Obese Subjects. Garner, RM., Mould, DR., Chieffo, C., et al.[2020]

Lipoxins, a type of eicosanoid, have unique anti-inflammatory properties that can significantly reduce airway hyperresponsiveness and inflammation in asthma, as shown in experimental models.

The administration of a stable analog of lipoxin A(4) not only decreased inflammation but also indicated that targeting lipoxin pathways could offer new therapeutic strategies for managing asthma and airway inflammation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exploring new approaches to the treatment of asthma: potential roles for lipoxins and aspirin-triggered lipid mediators. Levy, BD., Serhan, CN.[2019]

Nitrated fatty acids (NFAs), specifically 10-nitro-oleic acid (OA-NO2), have shown promise as an effective treatment for allergic airway disease in preclinical models, reducing disease severity and demonstrating unique mechanisms of action compared to traditional inhaled steroids.

Unlike fluticasone, which is a common inhaled steroid, OA-NO2 not only reduced inflammation but also induced apoptosis of neutrophils, suggesting it may be particularly beneficial for patients with severe asthma that is resistant to steroid treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The nitrated fatty acid 10-nitro-oleate attenuates allergic airway disease. Reddy, AT., Lakshmi, SP., Dornadula, S., et al.[2022]

The review highlights the role of polyunsaturated fatty acids (PUFAs) and their metabolites, such as eicosanoids and specialized pro-resolving lipid mediators (SPMs), in the chronic inflammation and bronchial obstruction associated with asthma.

Recent advances in lipidomics suggest that SPMs could be potential therapeutic agents for managing asthma by promoting the resolution of inflammation, offering a new avenue for treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pro-Resolving Lipid Mediators in the Pathophysiology of Asthma. Kytikova, O., Novgorodtseva, T., Denisenko, Y., et al.[2020]

Lipoxin A4 (LXA4) stable analogs, specifically ATLa and ZK-994, effectively reduced inflammation in allergen-driven models by preventing excessive accumulation and activation of immune cells like eosinophils and T lymphocytes, showing over 50% reduction in leukocyte trafficking at doses below 0.5 mg/kg.

Unlike the CysLT1 receptor antagonist montelukast, LXA4 analogs not only reduced inflammatory cytokines such as IL-4 and IL-13 but also demonstrated a unique mechanism of action, highlighting their potential as new therapeutic agents for managing allergic airway inflammation and hyper-responsiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lipoxin A4 stable analogs reduce allergic airway responses via mechanisms distinct from CysLT1 receptor antagonism. Levy, BD., Lukacs, NW., Berlin, AA., et al.[2021]

A new class of lipid mediators, including lipoxins, resolvins, protectins, and maresins, derived from polyunsaturated fatty acids, shows strong anti-inflammatory effects in both laboratory and animal studies.

These compounds have significant therapeutic potential for treating various inflammatory lung diseases, such as asthma, cystic fibrosis, and acute lung injury, addressing a critical need for effective anti-inflammatory treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pro-resolving lipid mediators in inflammatory lung diseases]. Eickmeier, O., Hilberath, JN., Zielen, S., et al.[2011]

Lipoxins (LXs) are important anti-inflammatory mediators derived from arachidonic acid metabolism, playing a crucial role in resolving inflammation in asthma, with their levels influenced by bronchial inflammation and glucocorticoid treatments.

Mild asthmatics have higher levels of lipoxin synthesis compared to severe asthmatics, suggesting that enhancing LX production in severe cases could be a potential therapeutic strategy for improving bronchial inflammation resolution.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lipoxins in asthma: potential therapeutic mediators on bronchial inflammation? Bonnans, C., Chanez, P., Chavis, C.[2013]

Individuals with severe asthma have significantly lower levels of Lipoxin A(4) (LXA(4)), a mediator that helps resolve inflammation, compared to those with nonsevere asthma, suggesting a potential deficiency in anti-inflammatory mechanisms.

The study found decreased expression of lipoxin biosynthetic enzymes and receptors in severe asthma, indicating that the inability to produce and respond to lipoxins may contribute to the persistent airway inflammation seen in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Airway lipoxin A4 generation and lipoxin A4 receptor expression are decreased in severe asthma. Planagumà, A., Kazani, S., Marigowda, G., et al.[2021]

Patients with severe asthma, whether they have aspirin-exacerbated respiratory disease (AERD) or not, show significantly lower levels of the anti-inflammatory molecule lipoxin A4 (LX A4), indicating a potential link between asthma severity and LX metabolism.

The study suggests that lower LX A4 levels in severe asthma patients could open up new treatment possibilities using LX analogues, as these patients may benefit from therapies that enhance LX A4 production.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lipoxin A4 levels in asthma: relation with disease severity and aspirin sensitivity. Celik, GE., Erkekol, FO., Misirligil, Z., et al.[2013]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03762395

Study Details | NCT03762395 | Anti Inflammatory Lipid ... This research will evaluate how a synthetic nitro-fatty acid (CXA-10, 10-nitro-octadec-9-enoic acid) suppresses the systemic and airway inflammation that ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10999349/

Weight Loss Interventions for Adults with Obesity-Related ... A phase II clinical trial is ongoing to evaluate the clinical effectiveness of CXA-10 (10-nitro-octadec-9-enoic acid) in treating patients with ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6853153/

Pharmacokinetic and Pharmacodynamic Effects of Oral CXA ... ☑ Nonclinical studies with 10‐nitro‐9(E)‐octadec‐9‐enoic acid (CXA‐10), a nitro fatty acid, demonstrated potential therapeutic effects in disease states in ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1089860320301592

Electrophilic nitrated fatty acids are potential therapeutic ... Several types of exposures can cause acute or chronic inflammatory reactions in the lungs often leading to asthma, pulmonary fibrosis, chronic ...

5. atsjournals.org atsjournals.org/doi/full/10.1164/rccm.202406-1166SO?role=tab

Obesity-related Asthma: A Pathobiology-based Overview of ... Although obesity-related asthma is associated with worse asthma outcomes, optimal treatment approaches for this complex phenotype are still ...

6. reporter.nih.gov reporter.nih.gov/project-details/11193225

LIMA: Lipid anti-Inflammatory Mediators in Asthma to reduce airway ... Current data encourages that, in the setting of obesity, CXA-10 will limit lung dysfunction, promote adaptive signaling responses and shift gut bacterial ...

7. reporter.nih.gov reporter.nih.gov/search/DXElJXH-oU-E_yzJSBr8XQ/project-details/11193225

RePORT RePORTER - National Institutes of Health (NIH) | This project provides a novel precision pharmacology therapy, oral CXA-10, for the treatment of obese asthma, a disease that responds poorly to standard asthma ...

8. nature.com nature.com/articles/s41598-021-96471-9

Nitroalkene fatty acids modulate bile acid metabolism and ... Based on this data, a clinical trial administering CXA-10 for 6 weeks is ongoing in obesity-associated asthma (NCT03762395). The present ...

9. sciencedirect.com sciencedirect.com/science/article/pii/S0022227525001166

Fatty acid nitroalkenes regulate intestinal lipid absorption Assessment of intestinal TAG uptake by 3H-triolein tracing in mice showed that 10-NO2-OA significantly reduced dietary fat absorption by 75%. Quantitation of ...