Xanthohumol microbiome and signature in healthy adults (the XMaS trial): a phase I triple-masked, placebo-controlled clinical trial

Abstract

Background Natural products may provide a source for the discovery and development of adjunctive pharmacological interventions to modulate the inflammatory pathways contributing to chronic disease. Xanthohumol, a flavonoid from the hops plant (Humulus lupulus), has antioxidant and anti-inflammatory properties and may act as a prebiotic to the intestinal microbiota. Xanthohumol is not currently approved as a drug by the US Food and Drug Administration (FDA), but is available as a dietary supplement and ingredient in medical foods. To formally test the safety of xanthohumol, a phase I clinical trial (“XMaS”) was designed and approved under an Investigational New Drug application to the US FDA. The main objective is to examine the clinical safety and subjective tolerability of xanthohumol in healthy adults compared to placebo. Additional aims are to monitor biomarkers related to inflammation, gut permeability, bile acid metabolism, routes, and in vivo products of xanthohumol metabolism, and to evaluate xanthohumol’s impact on gut microbial composition. Methods The safety and tolerability of xanthohumol in healthy adults will be evaluated in a triple-masked, randomized, placebo-controlled trial. Participants will be randomized to either 24 mg/day of xanthohumol or placebo for 8 weeks. Blood cell counts, hepatic and renal function tests, electrolytes, and self-reported health-related quality of life measures will be collected every 2 weeks. Participants will be queried for adverse events throughout the trial. Xanthohumol metabolites in blood, urine, and stool will be measured. Biomarkers to be evaluated include plasma tumor necrosis factor-alpha, various interleukins, soluble CD14, lipopolysaccharide-binding protein, fecal calprotectin, and bile acids to assess impact on inflammatory and gut permeability-related mechanisms in vivo. Stool samples will be analyzed to determine effects on the gut microbiome. Discussion This phase I clinical trial of xanthohumol will assess safety and tolerability in healthy adults, collect extensive biomarker data for assessment of potential mechanism(s), and provide comparison data necessary for future phase II trials in chronic disease(s). The design and robustness of the planned safety and mechanistic evaluations planned provide a model for drug discovery pursuits from natural products. Trial registration ClinicalTrials.gov NCT03735420. Registered on November 8, 2018

Xanthohumol Microbiome and Signature in Healthy Adults (the XMaS Trial): Safety and Tolerability Results of a Phase I Triple‐Masked, Placebo‐Controlled Clinical Trial

“…The detailed methodology has been published. [ 14 ] The protocol was approved by the institutional review board (IRB) at National University of Natural Medicine (IRB # RB9718), registered on ClinicalTrials.gov (NCT03735420), and was conducted according to the principles of the Declaration of Helsinki. Participants provided written informed consent prior to participation in the study.…”

“…The randomization and allocation concealment procedures were described in‐depth in the published protocol. [ 14 ] To ensure equal representation, randomization was stratified by biologic sex to ensure equal allocation to each group. Participants were excluded if they had a history of any chronic disease, were taking any prescription medications, or if they were taking any dietary supplements which could potentially modulate inflammatory pathways (such as flavonoids, XN or hops, curcumin or turmeric, ginger, quercetin, rosemary, fenugreek, white willow, devil's claw, or > 1 g per day of fish oil).…”

“…Stool, urine, and additional blood samples were also collected for identification and quantification of XN and XN‐derived metabolites, analysis of effects on gut microbiota, fecal calprotectin, bile acid metabolism, and biomarkers of inflammation as described in the published protocol. [ 14 ] However, these analyses are initiated but incomplete at the time of article submission.…”

Xanthohumol Is a Potent Pan-Inhibitor of Coronaviruses Targeting Main Protease

“…Xanthohumol inhibits HSV-1 with an IC 50 value of 2.7 µg/mL, HIV with an IC 50 value of ≈20.74 µg/mL, and CMV with an IC 50 value of 2.5 µg/mL [23,24]. Because of its potent utilization of its antioxidant and anti-inflammatory properties, Xanthohumol has been approved in clinical studies for the safety and subjective tolerability in healthy adults (NCT03735420) [25]. After the breakout of COVID-19, many researchers keep discussing the potent roles of Xanthohumol against SARS-CoV-2.…”

Correction to: Xanthohumol microbiome and signature in healthy adults (the XMaS trial): a phase I triple-masked, placebo-controlled clinical trial

“…Following publication of the original article [ 1 ], we were notified that in the first paragraph of the Interventions section (line 202), “Participants randomized to placebo will be administered 288 mg of rice protein, 133.4 mg microcrystalline cellulose” should read “Participants randomized to placebo will be administered 288 mg of rice protein,109.3 mg microcrystalline cellulose”.…”