Avenanthramide for Inflammation

(AvenActive Trial)

Overseen By Marianne Rufiange, PhD

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Montreal Heart Institute

Must not be taking: NSAIDs, Aspirin, others

Disqualifiers: Cardiovascular, Diabetes, Hypertension, others

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 4 weeks

96 Participants Needed

Trial Summary

What is the purpose of this trial?

Avenanthramides (AVA) are di-phenolic compounds found only in oats and are of interest due to suggested bioactivities, including antioxidant and anti-inflammatory effects in vitro and in vivo. Published data suggests that polyphenols can work as modifiers of signal transduction pathways to elicit their beneficial effects. These natural compounds express anti-inflammatory activity by modulation of pro-inflammatory gene expression such as cyclo-oxygenase, lipoxygenase, nitric oxide synthases and several pivotal cytokines, mainly by acting through nuclear factor-kappa B and mitogen-activated protein kinase signaling. The biomarkers of inflammation in blood, i.e., pro-inflammatory cytokines, chemokines, as well as other inflammatory markers (i.e., high sensitivity C-reactive protein) are of particular interest. Primary Objectives: * To assess the safety and tolerability of single ascending oral doses of avenanthramide in healthy subjects. * To assess the safety and tolerability of multiple ascending oral doses of avenanthramide in healthy subjects and subjects with elevated waist circumference and low-grade inflammation. Secondary Objectives: * To determine the pharmacokinetics of avenanthramide following single ascending oral doses in healthy subjects. * To compare the pharmacokinetics of avenanthramide following single oral dose in healthy subjects under fasting and fed conditions. * To determine the pharmacokinetics of avenanthramide following multiple ascending oral doses in healthy subjects. * To determine the pharmacokinetics of avenanthramide following multiple ascending oral doses in subjects with elevated waist circumference and low-grade inflammation.

Will I have to stop taking my current medications?

Yes, you will need to stop taking any prescription drugs (except contraceptive or hormone replacement therapy) and regular use of anti-inflammatory drugs like NSAIDs or aspirin at least 28 days before starting the trial.

What evidence supports the effectiveness of the treatment Avenanthramide for inflammation?

While there is no direct evidence from the provided research articles about Avenanthramide, similar natural compounds like polyphenols found in Opuntia species have shown anti-inflammatory effects. These compounds help reduce inflammation by affecting cell behavior and inflammatory substances, suggesting that plant-derived treatments can be effective against inflammation. ^{1 2 3 4 5}

Is avenanthramide safe for humans?

Avenanthramides, found in oats, have been studied for their anti-inflammatory and antioxidant properties, and they have shown no toxicity in human cell studies at certain concentrations. They are generally considered safe based on current research, but more studies in humans are needed to fully confirm their safety. ^{6 7 8 9 10}

What makes the treatment Avenanthramide unique for inflammation?

Avenanthramide is unique because it is a natural compound found only in oats, known for its strong anti-inflammatory and anti-itch properties. It works by inhibiting specific pathways in cells that lead to inflammation, making it different from many synthetic drugs. Additionally, it can be applied topically, which may offer a more direct and soothing effect on inflamed skin. ^{6 7 9 11 12}

Research Team

Jean-Claude Tardif, M.D

Principal Investigator

Montreal Heart Institute

Eligibility Criteria

Healthy adults or those with a larger waist and low-grade inflammation can join this trial. They must not smoke, use drugs, or have significant health issues. Women of childbearing age should use effective birth control, while men agree to contraception and no sperm donation for 90 days post-trial.

Inclusion Criteria

You agree to abstain from consuming oats for seven days before starting the medication and throughout the duration of the study.

You have no noted medical illness, physical abnormalities or concerning ECG readings.

My partner and I agree to use two forms of birth control if she can have children.

Exclusion Criteria

Subjects who took an Investigational Product (IP) in the 28 days prior to the first study drug administration

I have a stomach or intestine condition that affects how my body absorbs medicine.

I have not taken supplements like resveratrol or CoQ10 in the last 28 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive single and multiple ascending oral doses of avenanthramide to assess safety, tolerability, and pharmacokinetics

4 weeks

Multiple visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including changes in vital signs, adverse events, and laboratory parameters

4 weeks

Treatment Details

Interventions

• Avenanthramide

Trial Overview The trial is testing Avenanthramide (AVA), a compound from oats thought to reduce inflammation. Participants will take either AVA or a placebo in single or multiple doses to check safety, tolerability, and how the body processes it.

Participant Groups

Group I: Avenanthramide tablet single oral dose Active Control 1 Intervention

adaptive dose levels

Group II: Avenanthramide tablet multiple oral dose Active Control 1 Intervention

adaptive dose levels

Group III: Placebo to match Avenanthramide tablet single oral dose Placebo Group 1 Intervention

adaptive dose levels

Group IV: Placebo to match Avenanthramide tablet multiple oral dose Placebo Group 1 Intervention

adaptive dose levels

Avenanthramide is already approved in Canada for the following indications:

Approved in Canada as Avenanthramides for:

• Inflammation

Who Is Running the Clinical Trial?

Montreal Heart Institute

Lead Sponsor

Trials

125

Recruited

85,400+

The Montreal Health Innovations Coordinating Center (MHICC)

Collaborator

Trials

14

Recruited

10,900+

Ceapro Inc.

Collaborator

Trials

2

Recruited

360+

Ceapro Inc.

Industry Sponsor

Trials

2

Recruited

360+

Findings from Research

The methanol extract of Capparis ecuadorica leaves (MCE) significantly reduced inflammation in both LPS-stimulated RAW 264.7 cells and in a mouse model of atopic dermatitis, showing a decrease in key inflammatory markers and symptoms such as ear thickness and IgE concentration.

MCE treatment appears to work by suppressing the IL-4 cytokine and inhibiting the iNOS-mediated COX-2 induction pathway, as well as reducing inflammasome activation, suggesting a potential mechanism for its anti-inflammatory effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-inflammatory effects of Capparis ecuadorica extract in phthalic-anhydride-induced atopic dermatitis of IL-4/Luc/CNS-1 transgenic mice. Song, BR., Lee, SJ., Kim, JE., et al.[2021]

The hexane extract and lignan-rich fraction from Phyllanthus amarus showed significant anti-inflammatory effects by reducing paw swelling and neutrophil influx in a carrageenan-induced inflammation model.

Specific lignans, particularly niranthin, phyltetralin, and nirtetralin, were identified as the main active compounds responsible for these anti-inflammatory properties, suggesting their potential as therapeutic agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-inflammatory properties of extracts, fractions and lignans isolated from Phyllanthus amarus. Kassuya, CA., Leite, DF., de Melo, LV., et al.[2017]

Opuntia species, a type of cactus, contain various phenolic compounds like quercetin and kaempferol, which have demonstrated significant anti-inflammatory effects in both laboratory and animal studies.

These compounds may help modulate inflammation by affecting cell infiltration and the secretion of inflammatory mediators, supporting the traditional use of Opuntia in folk medicine for treating conditions like asthma and burns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phenolic Compounds' Occurrence in Opuntia Species and Their Role in the Inflammatory Process: A Review. Zeghbib, W., Boudjouan, F., Vasconcelos, V., et al.[2022]

A series of novel acanthoic acid analogs were synthesized, demonstrating strong anti-inflammatory effects.

The study provides insights into the mechanisms by which these analogs exert their anti-inflammatory properties, highlighting their potential as therapeutic agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthesis and anti-inflammatory effects of novel pimarane diterpenoid analogs. Suh, YG., Lee, KO., Moon, SH., et al.[2019]

Total glycosides of Acanthopanax Giraldii (TGA) significantly reduce the production of inflammatory markers prostaglandin E(2) (PGE(2)) and nitric oxide (NO) in mouse macrophages, with an inhibitory rate of 87% for PGE(2) at 100 mg/L.

TGA inhibits the expression of COX-2 mRNA, which is a key enzyme in the inflammatory process, while not affecting TNF-alpha levels, indicating a specific anti-inflammatory mechanism of action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-inflammatory mechanism of total glycosides of Acanthopanax Giraldii. Yuan, F., Chen, J., Xu, GM., et al.[2021]

A new high-performance liquid chromatography (HPLC) method was developed to analyze avenanthramides in oats, revealing that these compounds can make up to 20% of the total avenanthramides detected in oat products.

The study found that avenanthramide content in oat products ranged from 2 to 82 µg/g, leading to an estimated daily intake of 0.3 to 2.1 mg for oat consumers, which is significantly lower than the amounts used in previous studies examining their biological effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of avenanthramides in oat products and estimation of avenanthramide intake in humans. Pridal, AA., Böttger, W., Ross, AB.[2019]

New dimers of avenanthramide B were discovered in oat leaves after pathogen attack, indicating a potential role in plant defense mechanisms.

These dimers were formed through a reaction involving peroxidase and hydrogen peroxide, suggesting a specific biochemical pathway for their synthesis that could enhance our understanding of plant responses to stress.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New dimeric compounds of avenanthramide phytoalexin in oats. Okazaki, Y., Ishizuka, A., Ishihara, A., et al.[2022]

Avenanthramides, antioxidants found in oats, showed no toxicity to human aortic endothelial cells (HAEC) at concentrations up to 40 ng/ml, indicating their safety for potential therapeutic use.

The avenanthramide-enriched mixture significantly reduced the adhesion of monocytes to endothelial cells and suppressed the expression of key adhesion molecules and proinflammatory cytokines, suggesting their potential role in preventing atherosclerosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The antiatherogenic potential of oat phenolic compounds. Liu, L., Zubik, L., Collins, FW., et al.[2022]

Avenanthramides, compounds found in oats, have been shown to inhibit inflammation in skin cells at very low concentrations (as low as 1 part per billion), suggesting they play a key role in the soothing effects of oatmeal for skin irritation.

Topical application of avenanthramides significantly reduced inflammation and itching in mouse models, indicating their potential as effective anti-inflammatory agents for treating skin conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avenanthramides, polyphenols from oats, exhibit anti-inflammatory and anti-itch activity. Sur, R., Nigam, A., Grote, D., et al.[2022]

This study identified and characterized seven A-type avenanthramides (AVAs) from sprouted oat bran, with five of these compounds being isolated for the first time, highlighting their potential as unique phytochemicals in oats.

The A-type AVAs demonstrated anti-inflammatory properties similar to C-type AVAs, suggesting that both types of AVAs could be beneficial in reducing inflammation, which is important for health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quantitative Analysis and Anti-inflammatory Activity Evaluation of the A-Type Avenanthramides in Commercial Sprouted Oat Products. Hu, C., Tang, Y., Zhao, Y., et al.[2021]

Three new compounds derived from oat seeds were identified as amides of 4,5-dihydroxyanthranilic acid with caffeic, p-coumaric, and ferulic acids, showing potential as beneficial constituents of oats.

These compounds exhibited stronger antioxidant activity than traditional avenanthramides, suggesting that they may play a significant role in scavenging harmful free radicals, which could have health benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New series of avenanthramides in oat seed. Ishihara, A., Kojima, K., Fujita, T., et al.[2021]

Avenanthramide-C (2c), a compound found in oats, is extensively metabolized in mice and by human gut bacteria, producing eight metabolites that may have health benefits.

One of the major metabolites, dihydroavenanthramide-C (M6), shows greater anti-cancer activity against human colon cancer cells than 2c itself, indicating its potential as a bioactive compound.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oat avenanthramide-C (2c) is biotransformed by mice and the human microbiota into bioactive metabolites. Wang, P., Chen, H., Zhu, Y., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Anti-inflammatory effects of Capparis ecuadorica extract in phthalic-anhydride-induced atopic dermatitis of IL-4/Luc/CNS-1 transgenic mice. [2021]

2. Germany pubmed.ncbi.nlm.nih.gov

Anti-inflammatory properties of extracts, fractions and lignans isolated from Phyllanthus amarus. [2017]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Phenolic Compounds' Occurrence in Opuntia Species and Their Role in the Inflammatory Process: A Review. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Synthesis and anti-inflammatory effects of novel pimarane diterpenoid analogs. [2019]

5. China pubmed.ncbi.nlm.nih.gov

Anti-inflammatory mechanism of total glycosides of Acanthopanax Giraldii. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Analysis of avenanthramides in oat products and estimation of avenanthramide intake in humans. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

New dimeric compounds of avenanthramide phytoalexin in oats. [2022]

8. Ireland pubmed.ncbi.nlm.nih.gov

The antiatherogenic potential of oat phenolic compounds. [2022]

9. Germany pubmed.ncbi.nlm.nih.gov

Avenanthramides, polyphenols from oats, exhibit anti-inflammatory and anti-itch activity. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Quantitative Analysis and Anti-inflammatory Activity Evaluation of the A-Type Avenanthramides in Commercial Sprouted Oat Products. [2021]

11. England pubmed.ncbi.nlm.nih.gov

New series of avenanthramides in oat seed. [2021]

12. United States pubmed.ncbi.nlm.nih.gov

Oat avenanthramide-C (2c) is biotransformed by mice and the human microbiota into bioactive metabolites. [2023]