Xanthohumol Metabolism and Signature

Study Overview
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Brief Summary
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A pilot study to assess the safety and tolerability of oral xanthohumol in humans, to identify a biological signature of xanthohumol exposure, and to characterize the role of xanthohumol metabolism by intestinal microorganisms in that signature.

Detailed Description
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This is a double-masked, placebo controlled, randomized clinical trial of xanthohumol, which is a constituent of hops (Humulus lupulus). Hops and its constituents have a long history of use for a variety of conditions. However, knowledge is limited regarding the measurable biological markers of human exposure, and the role of xanthohumol metabolism by microorganisms present in the gut. This information is necessary for the development of xanthohumol as a potential therapeutic intervention in conditions such as inflammatory bowel disease.

Official Title
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Xanthohumol Metabolism and Signature (XMaS) in Healthy Adults

Conditions
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Healthy

Intervention / Treatment
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* Drug: Xanthohumol
* Drug: Placebo oral capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and Women aged 21-50 years Willing to take isolated xanthohumol as a dietary supplement for 8 weeks Willing to have blood drawn semi-weekly and to fast for 10-12 hours before blood draws Willing and able to collect semi-weekly stool samples at home Able to speak, read, and understand English Must be able to provide written informed consent Non-smokers (including tobacco and Cannabis products, combusted or vaporized) Exclusion Criteria: History of any chronic disease including, but not limited to: diabetes (type 1 or 2); uncontrolled hypertension; coronary artery disease resulting in angina; cardiovascular disease requiring percutaneous coronary intervention (PCI), bypass, or past myocardial infarction or stroke; blood disease including current anemia; cancer (except non-melanoma skin cancer) within the last year or still requiring chemotherapy or hormonal therapy; chronic kidney disease; liver disease including viral hepatitis, non-alcoholic fatty liver disease, or alcoholic hepatitis/cirrhosis; any immunocompromising condition including human immunodeficiency virus/acquired immunodeficiency syndrome or organ transplant requiring anti-rejection medications; chronic osteoarthritis requiring joint replacement or daily use of NSAIDs; chronic endocrine condition including but not limited to: Cushing's, Addison's, Hashimoto's thyroiditis, Grave's disease, etc. Body Mass Index (BMI) less than 20 (underweight) or greater than 30 (obese) Consumption of more than 1 microbrew beer per day Use of NSAIDs more than once per week for headaches, routine aches/pains, etc. Use of any prescription drugs, including oral contraceptives (due to potential interference with mechanisms under investigation) Use of prescription opioids for any reason within the past 3 months Use of prescription corticosteroids for any reason within the past 3 months Free of acute viral or bacterial infection, or recent infection within the last 14 days or still requiring prescription medication for treatment Free of recent acute trauma occurring within the last 14 days Currently or recently (within last 14 days) taking any dietary supplements containing xanthohumol flavonoids, or other known herbal anti-inflammatories including: curcumin, turmeric, fenugreek, hops, rosemary, ginger, white willow, Devil's claw, fish oil (doses>1 g/day), or quercetin. Candidates will be given the option to wash out for 14 days and re-contact the study team. Currently receiving intravenous nutrition support therapy (or within the last 30 days) Currently taking anti-coagulant or anti-platelet prescription medications (or they were taken within the last 30 days) Currently taking antibiotic, antiparasitic, or antifungal medications orally or intravenously (or they were taken within the last 30 days) Initiation of or changes to supplements or medications within 30 days prior to screening Initiation of or changes to an exercise regimen within 30 days prior to screening Initiation of or changes to a food plan within 30 days prior to screening Current involvement or within 30 days prior to screening of a significant diet or weight loss program, such as NutriSystem, Jenny Craig, Atkin's or other low-carb diet programs, or very low-calorie liquid diet programs (such as optifast, medifast, and/or HMR) Hospitalization (for any reason other than an elective medical procedure) within 3 months prior to screening Gastrointestinal surgery within 3 months prior to screening Undergoing UV therapy (e.g. treatment for skin conditions such as psoriasis). Engaging in vigorous exercise more than 6 hours per week. Women who are lactating, pregnant or planning pregnancy within the next four months Typical intake of more than 2 alcohol-containing beverages per day, more than 14 per week, or more than 4 in any single day within the past 28 days Use of recreational drugs/substances (such as but not limited to cocaine, phencyclidine (PCP), and methamphetamine) within 30 days of screening Currently participating in another interventional research study or participated in another interventional study within 30 days of screening

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be randomized to receive either encapsulated xanthohumol in a rice protein vehicle, or an identical capsule containing vehicle alone.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Xanthohumol<br>Participants will receive 24 mg of 98% pure xanthohumol in a rice protein vehicle by mouth once daily with the first daily meal. | Drug: Xanthohumol<br>* The xanthohumol supplement will be administered in a capsule. Participants in the experimental arm will consume the capsule once per day, with the first meal. The intervention will extend for 8 weeks.<br>|
| Placebo Comparator: Placebo oral capsule<br>Participants will receive vehicle (rice protein) by mouth once daily with the first daily meal. | Drug: Placebo oral capsule<br>* The placebo (vehicle) will be administered in a capsule. Participants in the placebo arm will consume the capsule once per day, with the first meal.<br>* Other names: Vehicle;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Plasma Inflammatory Markers | Circulating pro-inflammatory cytokine concentrations (tumor necrosis factor (TNF)-α, interleukin (IL)-1 beta, IL-6, IL-8, IL-10, and IL-12p70), will be measured simultaneously with a flow cytometry-based multiplex assay. The measures were assessed at Baseline, 2 weeks, 4 weeks, 6 weeks, and 8 weeks; weeks 2, 4, 6, and 8 reported | 2 weeks, 4 weeks, 6 weeks, and 8 weeks. | 
| Incidence of Intervention-attributable Adverse Events [Safety and Tolerability] | Self-reported adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events. Reported as: New onset FDA serious adverse events (Grade 1); New onset moderate adverse events (Grade 2). The measures were assessed at Baseline, 2 weeks, 4 weeks, 6 weeks, and 8 weeks; weeks 2, 4, 6, and 8 reported. | Baseline, 2 weeks, 4 weeks, 6 weeks, and 8 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Levels of Metabolic Byproducts of Xanthohumol: Plasma and Urine | Xanthohumol and xanthohumol metabolites in blood, urine and stool, will be measured by ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry. Metabolites include 6-prenylnaringenin (6-PN), 8-prenylnaringenin (8-PN), dihydroxanthohumol (DXN), desmethyldihydroxanthohumol (DDXN), isoxanthohumol (IXN), and xanthohumol (XN). The measures were assessed at Baseline, 2 weeks, 4 weeks, 6 weeks, and 8 weeks; baseline, weeks 2, 4, 6, and 8 reported for urine and plasma. | Baseline, 2 weeks, 4 weeks, 6 weeks, and 8 weeks. | 
| Change in Levels of Metabolic Byproducts of Xanthohumol: Stool | Xanthohumol and xanthohumol metabolites in blood, urine and stool, will be measured by ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry. Metabolites include 6-prenylnaringenin (6-PN), 8-prenylnaringenin (8-PN), dihydroxanthohumol (DXN), desmethyldihydroxanthohumol (DDXN), isoxanthohumol (IXN), and xanthohumol (XN). The measures were assessed at Baseline, 2 weeks, 4 weeks, 6 weeks, and 8 weeks; baseline, weeks 2, 4, 6, and 8 reported for urine and plasma. As stool metabolites have not yet been analyzed, data will be released upon assessment. | Baseline, 2 weeks, 4 weeks, 6 weeks, and 8 weeks. | 
| Bile Acids | Bile acid concentrations in blood and feces, will be measured by ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry, and expressed as mean change over time from baseline. | Baseline, 2 weeks, 4 weeks, 6 weeks, and 8 weeks. | 
| Gut Inflammation | Fecal calprotectin, a protein associated with gut inflammation and irritable gut syndrome, will be measured by enzyme-linked immunosorbent assay, and expressed as mean change over time from baseline. | Baseline, 2 weeks, 4 weeks, 6 weeks, and 8 weeks. | 
| Aspartate Aminotransferase (AST) | Aspartate aminotransferase is an enzyme that is often measured in blood as an indication of liver toxicity. Reported as mean change from baseline. | 2 weeks, 4 weeks, 6 weeks, and 8 weeks. | 
| Alanine Aminotransferase (ALT) | Alanine aminotransferase is an enzyme that is often measured in blood as an indication of liver toxicity. Reported as mean change from baseline. | 2 weeks, 4 weeks, 6 weeks, and 8 weeks. | 
| Gamma-Glutamyl Transferase (GGT) | Gamma-glutamyl transferase is an enzyme that is often measured in blood as an indication of liver toxicity. Reported as mean change from baseline. | Baseline, 2 weeks, 4 weeks, 6 weeks, and 8 weeks | 
| Estimated Glomerular Filtration Rate | Glomerular filtration rate is estimated based on blood creatinine concentration per standard nephrology practice. Reported as mean change from baseline. | 2 weeks, 4 weeks, 6 weeks, and 8 weeks | 
| Blood Urea Nitrogen to Creatinine Ratio | Blood urea nitrogen (BUN) : creatinine (Cr) is a ratio of serum concentrations of two compounds associated with renal function. Reported as mean change from baseline. | 2 weeks, 4 weeks, 6 weeks, and 8 weeks. | 
| Complete Blood Count Abnormals | Enumeration of the various subtypes of blood cells (i.e., red blood cells, white blood cells, and platelets), plus indices including mean corpuscular hemoglobin (MCH), mean corpuscular volume (MCV), and hematocrit. Reported as: % abnormal (i.e., number of participants with an abnormal value compared to the number of participants in the group) and % new abnormals if abnormal counts were noted. Abnormality is assessed according to standards for age and sex measurements under Quest Diagnostics criteria. | 2 weeks, 4 weeks, 6 weeks, and 8 weeks. | 
| Total Red Blood Cell Count | Enumeration of total red blood cell count. Reported as mean change from baseline. | Baseline, 2 weeks, 4 weeks, 6 weeks, and 8 weeks. | 
| Total White Blood Cell Count | Enumeration of total white blood cell count. Results are reported as mean change from baseline at weeks 2, 4, 6, and 8. | 2 weeks, 4 weeks, 6 weeks, and 8 weeks. | 
| Platelet Count | Enumeration of platelet count. Results are reported as mean change from baseline at weeks 2, 4, 6, and 8. | 2 weeks, 4 weeks, 6 weeks, and 8 weeks. | 
| Mean Corpuscular Volume | Enumeration of mean corpuscular volume (MCV). Results are reported as mean change from baseline at weeks 2, 4, 6, and 8. | 2 weeks, 4 weeks, 6 weeks, and 8 weeks. | 
| Mean Corpuscular Hemoglobin | Enumeration of mean corpuscular hemoglobin (MCH). Results are reported as mean change from baseline at weeks 2, 4, 6, and 8. | 2 weeks, 4 weeks, 6 weeks, and 8 weeks. | 
| Hematocrit | Enumeration of hematocrit. Results are reported as mean change from baseline at weeks 2, 4, 6, and 8. | 2 weeks, 4 weeks, 6 weeks, and 8 weeks. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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xanthohumol, gut microbiome, inflammation