Clinical trial NCT06101784: Single and Multiple Ascending Oral Doses of Avenanthramide
Official title: A Double-Blind, Placebo-Controlled, Randomized, Adaptive, First-in-Human Study to Assess Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Oral Doses of Avenanthramide
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Inflammation
Keywords: Healthy subjects
Single ascending dose
Multiple ascending dose
Natural product
Placebo controlled
First in human
Lead sponsor: Montreal Heart Institute
Sponsor class: OTHER
Collaborators: name: Ceapro Inc.
name: The Montreal Health Innovations Coordinating Center (MHICC)
First posted: 2023-10-26
Enrollment: 96
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Double-Blind, Placebo-Controlled, Randomized, Adaptive, First-in-Human Study, Single and Multiple Ascending Oral Doses
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

* 1. Male or female subjects;
* 2. Body mass index (BMI) within 18.5 kg/m2 to 30.0 kg/m2, inclusively, for subjects participating in Part A and Part B;
* 3. Age 18-60 years;
* 4. Willing to avoid rigorous physical activity 1 day prior to the first drug administration and during study participation;
* 5. Willing to avoid oat consumption for 1 week prior to the first drug administration and during study participation;
* 6. Non- or ex-smoker; an ex-smoker is defined as someone who completely stopped using nicotine products for at least 6 months prior to the first study drug administration;
* 7. Non- or ex-consumer of cannabis; an ex-consumer of cannabis is defined as someone who stopped using cannabis derived products for at least 6 months prior to the first study drug administration;
* 8. Have no clinically significant diseases captured in the medical history and no evidence of clinically significant findings on the physical examination (including vital signs) and/or ECG, as determined by the investigator;
* 9. Clinical laboratory values within the laboratory's stated normal range; if not within this range, they must be without clinical significance, as determined by the investigator;
* 10. Provision of signed and dated informed consent form (ICF);
* 11. Stated willingness to comply with all study procedures and availability for the duration of the study;
* 12. A male subject meeting one of the following criteria:

  1. Subject is able to procreate and agrees to use one of the accepted contraceptive regimens and not donate sperm from the first study drug administration to at least 90 days after the last drug administration. An acceptable method of contraception includes one of the following:

     * True abstinence from heterosexual intercourse when this is in line with the preferred and usual lifestyle of the subject (not periodic abstinence)
     * Male condom with spermicide or male condom with a vaginal spermicide (gel, foam, or suppository) If the subject has a partner of childbearing potential, he and/or his partner must agree to use two acceptable birth control methods.

     Or
  2. Subject is unable to procreate; defined as surgically sterile (i.e., has undergone a vasectomy at least 6 months prior to the first study drug administration)
* 13. A female subject meeting one of the following criteria:

  1. Subject of childbearing potential must agree to use an effective double method of birth control from the first study drug administration to at least 30 days after the last drug administration: barrier method (e.g., male or female condoms, spermicides, sponges, foams, jellies, and diaphragm) in combination with other methods of contraception including implantable contraceptives, injectable contraceptives, oral contraceptives, transdermal contraceptives, intrauterine devices; or must have a sterile sexual partner.

     Or
  2. Subject is of childbearing potential and agrees to abide by true abstinence from heterosexual intercourse, when this is in line with the preferred and usual lifestyle of the subject (not periodic abstinence) Or
  3. Subject is of non-childbearing potential, defined as surgically sterile (i.e., has undergone complete hysterectomy, bilateral oophorectomy, or tubal ligation) or is in a menopausal state (i.e., at least 1 year without menses prior to the first study drug administration).
* Part-C:

Inclusion Criteria modified:

In addition to the above criteria, the inclusion criterion #2 is defined as following:

2\*. Body mass index (BMI) within 18.5 kg/m2 to 34.0 kg/m2, inclusively, for the subjects participating in Part C.

Also, subjects with elevated waist circumference and low-grade inflammation must meet the following criteria in order to be included in the study:

* Waist circumference ≥ 100 cm in men and ≥ 85 cm in women
* Hs-CRP equal or greater than 2.0 mg/L and less than 10.0 mg/L at Screening

Exclusion Criteria:

* 1. Allergy to any ingredient of the Investigational Products, including excipients;
* 2. Oat products consumption within 1-week prior the first drug administration;
* 3. History of significant hypersensitivity to any excipients of the formulation, as well as severe hypersensitivity reactions (like angioedema) to any drug;
* 4. Presence of significant gastrointestinal (GI) conditions that interfere with absorption;
* 5. Presence of significant cardiovascular disease, gastrointestinal disease, kidney disease, or endocrine disease: including diabetes, and untreated thyroid disease, or rheumatoid arthritis;
* 6. Diagnosis of Gilbert syndrome;
* 7. Systolic blood pressure \> 150 mmHg and/or diastolic blood pressure \> 95 mmHg at screening;
* 8. Major trauma or surgery within 3 months of study participation;
* 9. Presence of clinically significant ECG abnormalities at the screening, as defined by medical judgment;
* 10. Any clinically significant illness in the 28 days prior to the first study drug administration;
* 11. Any history of tuberculosis or proven contact with tuberculosis;
* 12. Positive test result for alcohol and/or drugs of abuse at screening or prior to the first drug administration;
* 13. Positive screening results to HIV Ag/Ab Combo, Hepatitis B surface Antigen (HbsAg (B) (hepatitis B)) or Hepatitis C Virus (HCV (C)) tests at screening;
* 14. Active treatment for any type of cancer, except basal cell carcinoma, within 1 year prior to the first drug administration;
* 15. Use of any prescription drugs (with the exception of contraceptive or hormone replacement therapy) in the 28 days prior to the first study drug administration;
* 16. Regular use of anti-inflammatory drugs such as NSAIDs or aspirin in the 28 days prior to the first study drug administration;
* 17. Rigorous physical activity the day prior the first drug administration;
* 18. Nicotine smoking and/or nicotine replacement use;
* 19. Drinking alcohol \>10 drinks/week, or history of drug abuse;
* 20. Strict dietary restrictions (such as ketogenic or vegan diet);
* 21. Regular use of nutraceuticals such as resveratrol, immune boosters, glucosamine, chondroitin, Coenzyme Q10 supplementation in the 28 days prior to the first study drug administration;
* 22. Regular use of plant concentrates (including garlic, gingko, St. John's wort) homeopathic remedies, probiotics, or fish oil (including cod liver oil), in the 28 days prior to the first drug administration;
* 23. Females who are lactating or are pregnant according to the pregnancy test at screening or prior to the first study drug administration;
* 24. Subjects who have already been included in a previous group/cohort for this clinical study;
* 25. Subjects who took an Investigational Product (IP) in the 28 days prior to the first study drug administration;
* 26. Subjects who donated 50 mL and up to 450 mL of blood in the 28 days prior to the first study drug administration;
* 27. Donation of 450 mL or more of blood (Canadian Blood Services, Hema Quebec, clinical studies, etc.) in the 2 months prior to the first study drug administration for males, and in the 3 months prior to the first drug administration for females.

Primary outcomes:
measure: Incidence of Adverse Events (Safety and Tolerability)
timeFrame: from drug administration up to 24 hours after the last dose
measure: Change in laboratory parameters (general biochemistry)
timeFrame: from drug administration up to 24 hours after the last dose
measure: Change in laboratory parameters (general biochemistry)
timeFrame: from drug administration up to 24 hours after the last dose
measure: Change in laboratory parameters (general biochemistry)
timeFrame: from drug administration up to 24 hours after the last dose
measure: Change in laboratory parameters (general biochemistry)
timeFrame: from drug administration up to 24 hours after the last dose
measure: Change in laboratory parameters (general biochemistry)
timeFrame: from drug administration up to 24 hours after the last dose
measure: Change in laboratory parameters (general biochemistry)
timeFrame: from drug administration up to 24 hours after the last dose
measure: Change in laboratory parameters (general biochemistry)
timeFrame: from drug administration up to 24 hours after the last dose
measure: Change in laboratory parameters (general biochemistry)
timeFrame: from drug administration up to 24 hours after the last dose
measure: Change in laboratory parameters (general biochemistry)
timeFrame: from drug administration up to 24 hours after the last dose
measure: Change in laboratory parameters (general biochemistry)
timeFrame: from drug administration up to 24 hours after the last dose
measure: Change in laboratory parameters (general biochemistry)
timeFrame: from drug administration up to 24 hours after the last dose
measure: Change in laboratory parameters (general biochemistry)
timeFrame: from drug administration up to 24 hours after the last dose
measure: Change in laboratory parameters (hematology)
timeFrame: from drug administration up to 24 hours after the last dose
measure: Change in laboratory parameters (hematology)
timeFrame: from drug administration up to 24 hours after the last dose
measure: Change in laboratory parameters (hematology)
timeFrame: from drug administration up to 24 hours after the last dose
measure: Change in laboratory parameters (hematology)
timeFrame: from drug administration up to 24 hours after the last dose
measure: Change in laboratory parameters (hematology)
timeFrame: from drug administration up to 24 hours after the last dose
measure: Change in laboratory parameters (hematology)
timeFrame: from drug administration up to 24 hours after the last dose
measure: Change in laboratory parameters (hematology)
timeFrame: from drug administration up to 24 hours after the last dose
measure: Change in laboratory parameters (hematology)
timeFrame: from drug administration up to 24 hours after the last dose
measure: Change in laboratory parameters (hematology)
timeFrame: from drug administration up to 24 hours after the last dose
measure: Change in physical examination (Safety and Tolerability)
timeFrame: from drug administration up to 24 hours after the last dose
measure: Change in physical examination (Safety and Tolerability)
timeFrame: from drug administration up to 24 hours after the last dose
measure: Change in physical examination (Safety and Tolerability)
timeFrame: from drug administration up to 24 hours after the last dose
measure: Change in physical examination (Safety and Tolerability)
timeFrame: from drug administration up to 24 hours after the last dose
measure: Change in physical examination (Safety and Tolerability)
timeFrame: from drug administration up to 24 hours after the last dose
measure: Change in physical examination (Safety and Tolerability)
timeFrame: from drug administration up to 24 hours after the last dose
measure: Change in vital signs (Safety and Tolerability)
timeFrame: from drug administration up to 24 hours after the last dose
measure: Change in vital signs (Safety and Tolerability)
timeFrame: from drug administration up to 24 hours after the last dose
measure: Change in vital signs (Safety and Tolerability)
timeFrame: from drug administration up to 24 hours after the last dose
measure: Change in ECG parameters (Safety and Tolerability)
timeFrame: from drug administration up to 24 hours after the last dose
measure: Change in ECG parameters (Safety and Tolerability)
timeFrame: from drug administration up to 24 hours after the last dose
measure: Change in ECG parameters (Safety and Tolerability)
timeFrame: from drug administration up to 24 hours after the last dose
Secondary outcomes:
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
measure: The change in Pharmacokinetics
timeFrame: Up to 24 hours after the last dose
Other outcomes:
Locations:
city: Montréal
country: Canada
facility: Montreal Heart Institute
state: Quebec
Study officials:
affiliation: Montreal Heart Institute
name: Jean-Claude Tardif, MD
role: PRINCIPAL_INVESTIGATOR
References: