Clinical trial NCT06225258: Xanthohumol As an Adjuvant in the Treatment of Septic Shock
Official title: Analysis of Anti-inflammatory Effect of Hop Extract Rich in Xanthohumol in Patients Treated for Septic Shock
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Septic Shock
Pneumonia
ARDS
Keywords: septic shock
inflammation
Xanthohumol
adjuvant
endotheliopathy
ARDS
Lead sponsor: Medical University of Lublin
Sponsor class: OTHER
First posted: 2024-01-25
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients are randomised in a double-blind, placebo-controlled manner to two groups using sealed envelopes. In the intervention group, all patients receive Xanthohumol as adjunctive therapy as recommended by the Surviving Sepsis Campaign. In the control group, patients are treated without Xanthohumol as recommended by the Surviving Sepsis Campaign and are treated as recommended by Surviving Sepsis.

Bioavailability, clinical and possible side effects are monitored.
Primary purpose: TREATMENT

Brief summary: Septic shock (SS) is a life-threatening condition resulting from excessive inflammatory response to bacterial, viral or/and fungal infections. It is associated with dysregulation of the immune system, activation of immune cells, and massive release of cytokines, commonly known as the cytokine storm (CS). The clinical manifestations of SS depend on the initial site of infection. However, the classic symptoms are associated with severe dysfunction of the respiratory and cardiovascular systems, which are observed from the early phase. Respiratory insufficiency frequently requires different forms of oxygen supplementation, including mechanical ventilation and even extracorporeal oxygenation. The severity of respiratory and other organ dysfunction depends on the inflammatory response to the infection and circulating toxins, which correspond to excessive cytokine release. In the past years, several studies documented that reduction of SS-related inflammatory response and CS improved organ function and alleviated the clinical course of SS. Unfortunately, an effective strong anti-inflammatory without side effects medications has not yet been found. Therefore, the use of natural anti-inflammatory and antioxidant substances seems very promising.

Xanthohumol (Xn) is a natural prenylated chalcone extracted from the female inflorescences of hop cones (Humulus lupus) and possesses strong anti-inflammatory and antioxidant properties. It is widely used as a supplement to diet. Xanthohumol inhibits CS and has been showed to be an effective medication for reducing the severity of lung injury. It has been documented that Xn inhibits proinflammatory pathways in a different manner. A decrease in cytokine production and release can affect endothelial function and correct inflammatory-related vascular hyperpermeability, reducing uncontrolled water shift to extravascular space and then tissue edema. Clinical observation showed that administration of Xn alleviated clinical course, improved respiratory function, and reduced mortality in critically ill COVID-19 patients. Xanthohumol is safe and well tolerated by humans, and no adverse effects have been reported yet. Based on its strong anti-inflammatory and antioxidative properties, it can be speculated that the use of Xn can effectively reduce the inflammatory response and improve the clinical course in SS patients.


Eligibility criteria: Inclusion Criteria:

* a septic shock in the early, acute phase,
* respiratory insufficiency required mechanical ventilation with PaO2/FiO2 \< 150,
* bacterial infection,
* procalcitonin higher than 5 ng/mL and interleukin 6 higher than 100 pg/mL,
* no allergy to hops or their derivatives,
* hemodynamic instability requiring vasopressor infusions

Exclusion Criteria:

* lack of agreement
* septic shock treated for more than 1 day,
* history of severe chronic cardiac, pulmonary and/or liver diseases

Primary outcomes:
measure: Xanthohumol as an adjunctive treatment improves clinical course in ill septic shock patents
timeFrame: 7 and 28 days mortality
measure: Xanthohumol as an adjunctive treatmenty affects a severity of inflammation
timeFrame: 7 time points: just after ICU admission and on the days 1,2,3,4,5 and 6 after ICU admission.
measure: Xanthohumol as an adjunctive treatment affects sepsis-related glycocalyx injury
timeFrame: 7 time points: just after ICU admission and on the days 1,2,3,4,5 and 6 after ICU admission.
Secondary outcomes:
measure: Xanthohumol as an adjunctive treatment affects plasma interleukin 1beta concentration.
timeFrame: 7 time points: just after ICU admission and on the days 1,2,3,4,5 and 6 after ICU admission.
measure: Xanthohumol as an adjunctive treatment changes plasma tumor necrosis factor-alpha concentration.
timeFrame: 7 time points: just after ICU admission and on the days 1,2,3,4,5 and 6 after ICU admission.
measure: Xanthohumol as an adjunctive treatment affects plasma interleukin 6 concentration.
timeFrame: 7 time points: just after ICU admission and on the days 1,2,3,4,5 and 6 after ICU admission.
measure: Xanthohumol as an adjunctive treatment affects plasma interleukin 8 concentration.
timeFrame: 7 time points: just after ICU admission and on the days 1,2,3,4,5 and 6 after ICU admission.
measure: Xanthohumol as an adjunctive treatment affects plasma syndecan 1 concentration.
timeFrame: 7 time points: just after ICU admission and on the days 1,2,3,4,5 and 6 after ICU admission.
measure: Xanthohumol as an adjunctive treatment affects plasma vascular endothelial adhesion molecule 1 concentration.
timeFrame: 7 time points: just after ICU admission and on the days 1,2,3,4,5 and 6 after ICU admission.
measure: Xanthohumol as an adjunctive treatment affects plasma E-selectin concentration.
timeFrame: 7 time points: just after ICU admission and on the days 1,2,3,4,5 and 6 after ICU admission.
measure: Xanthohumol as an adjunctive treatment affects plasma vascular endothelial growth factor concentration.
timeFrame: 7 time points: just after ICU admission and on the days 1,2,3,4,5 and 6 after ICU admission.
Other outcomes:
Locations:
city: Lublin
country: Poland
facility: Intensive Care Unit, University Hospital No 4,
Study officials:
affiliation: Medical University of Lublin, Poland
name: Wojciech Dabrowski, Prof
role: STUDY_CHAIR
affiliation: Medical University of Lublin, Poland
name: Wlodzimierz Plotek
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bartmanska A, Tronina T, Poplonski J, Huszcza E. Biotransformations of prenylated hop flavonoids for drug discovery and production. Curr Drug Metab. 2013 Dec;14(10):1083-97. doi: 10.2174/1389200214666131211151855.
citation: Bosmann M, Ward PA. The inflammatory response in sepsis. Trends Immunol. 2013 Mar;34(3):129-36. doi: 10.1016/j.it.2012.09.004. Epub 2012 Oct 2.
citation: Chen X, Li Z, Hong H, Wang N, Chen J, Lu S, Zhang H, Zhang X, Bei C. Xanthohumol suppresses inflammation in chondrocytes and ameliorates osteoarthritis in mice. Biomed Pharmacother. 2021 May;137:111238. doi: 10.1016/j.biopha.2021.111238. Epub 2021 Jan 28.
citation: Corrado C, Barreca MM, Raimondo S, Diana P, Pepe G, Basilicata MG, Conigliaro A, Alessandro R. Nobiletin and xanthohumol counteract the TNFalpha-mediated activation of endothelial cells through the inhibition of the NF-kappaB signaling pathway. Cell Biol Int. 2023 Mar;47(3):634-647. doi: 10.1002/cbin.11963. Epub 2022 Nov 15.
citation: Costa R, Negrao R, Valente I, Castela A, Duarte D, Guardao L, Magalhaes PJ, Rodrigues JA, Guimaraes JT, Gomes P, Soares R. Xanthohumol modulates inflammation, oxidative stress, and angiogenesis in type 1 diabetic rat skin wound healing. J Nat Prod. 2013 Nov 22;76(11):2047-53. doi: 10.1021/np4002898. Epub 2013 Nov 7.
citation: Dabrowski W, Gagos M, Siwicka-Gieroba D, Piechota M, Siwiec J, Bielacz M, Kotfis K, Stepulak A, Grzycka-Kowalczyk L, Jaroszynski A, Malbrain ML. Humulus lupus extract rich in xanthohumol improves the clinical course in critically ill COVID-19 patients. Biomed Pharmacother. 2023 Feb;158:114082. doi: 10.1016/j.biopha.2022.114082. Epub 2022 Dec 9.
citation: Dartiguelongue JB. Systemic inflammation and sepsis. Part I: Storm formation. Arch Argent Pediatr. 2020 Dec;118(6):e527-e535. doi: 10.5546/aap.2020.eng.e527. English, Spanish.
citation: Chong DLW, Sriskandan S. Pro-inflammatory mechanisms in sepsis. Contrib Microbiol. 2011;17:86-107. doi: 10.1159/000324022. Epub 2011 Jun 9.
citation: Gaudette S, Smart L, Woodward AP, Sharp CR, Hughes D, Bailey SR, Dandrieux JRS, Santos L, Boller M. Biomarkers of endothelial activation and inflammation in dogs with organ dysfunction secondary to sepsis. Front Vet Sci. 2023 Jul 13;10:1127099. doi: 10.3389/fvets.2023.1127099. eCollection 2023.
citation: Girisa S, Saikia Q, Bordoloi D, Banik K, Monisha J, Daimary UD, Verma E, Ahn KS, Kunnumakkara AB. Xanthohumol from Hop: Hope for cancer prevention and treatment. IUBMB Life. 2021 Aug;73(8):1016-1044. doi: 10.1002/iub.2522. Epub 2021 Jul 6.
citation: Jung F, Staltner R, Tahir A, Baumann A, Burger K, Halilbasic E, Hellerbrand C, Bergheim I. Oral intake of xanthohumol attenuates lipoteichoic acid-induced inflammatory response in human PBMCs. Eur J Nutr. 2022 Dec;61(8):4155-4166. doi: 10.1007/s00394-022-02964-2. Epub 2022 Jul 20.
citation: Lee IS, Lim J, Gal J, Kang JC, Kim HJ, Kang BY, Choi HJ. Anti-inflammatory activity of xanthohumol involves heme oxygenase-1 induction via NRF2-ARE signaling in microglial BV2 cells. Neurochem Int. 2011 Feb;58(2):153-60. doi: 10.1016/j.neuint.2010.11.008. Epub 2010 Nov 18.
citation: Li F, Yao Y, Huang H, Hao H, Ying M. Xanthohumol attenuates cisplatin-induced nephrotoxicity through inhibiting NF-kappaB and activating Nrf2 signaling pathways. Int Immunopharmacol. 2018 Aug;61:277-282. doi: 10.1016/j.intimp.2018.05.017. Epub 2018 Jun 12.
citation: Lin Y, Zang R, Ma Y, Wang Z, Li L, Ding S, Zhang R, Wei Z, Yang J, Wang X. Xanthohumol Is a Potent Pan-Inhibitor of Coronaviruses Targeting Main Protease. Int J Mol Sci. 2021 Nov 9;22(22):12134. doi: 10.3390/ijms222212134.
citation: Luescher S, Urmann C, Butterweck V. Effect of Hops Derived Prenylated Phenols on TNF-alpha Induced Barrier Dysfunction in Intestinal Epithelial Cells. J Nat Prod. 2017 Apr 28;80(4):925-931. doi: 10.1021/acs.jnatprod.6b00869. Epub 2017 Feb 24.
citation: Nolan A, Weiden MD, Thurston G, Gold JA. Vascular endothelial growth factor blockade reduces plasma cytokines in a murine model of polymicrobial sepsis. Inflammation. 2004 Oct;28(5):271-8. doi: 10.1007/s10753-004-6050-3.
citation: Rahman SU, Ali T, Hao Q, He K, Li W, Ullah N, Zhang Z, Jiang Y, Li S. Xanthohumol Attenuates Lipopolysaccharide-Induced Depressive Like Behavior in Mice: Involvement of NF-kappaB/Nrf2 Signaling Pathways. Neurochem Res. 2021 Dec;46(12):3135-3148. doi: 10.1007/s11064-021-03396-w. Epub 2021 Aug 16.
citation: Stevens JF, Page JE. Xanthohumol and related prenylflavonoids from hops and beer: to your good health! Phytochemistry. 2004 May;65(10):1317-30. doi: 10.1016/j.phytochem.2004.04.025.
citation: Tang Z, Feng Y, Nie W, Li C. Xanthohumol attenuates renal ischemia/reperfusion injury by inhibiting ferroptosis. Exp Ther Med. 2023 Oct 24;26(6):571. doi: 10.3892/etm.2023.12269. eCollection 2023 Dec.
citation: Xiao-Lei S, Tian-Shuang X, Yi-Ping J, Na-Ni W, Ling-Chuan X, Ting H, Hai-Liang X. Humulus lupulus L. extract and its active constituent xanthohumol attenuate oxidative stress and nerve injury induced by iron overload via activating AKT/GSK3beta and Nrf2/NQO1 pathways. J Nat Med. 2023 Jan;77(1):12-27. doi: 10.1007/s11418-022-01642-1. Epub 2022 Sep 8.
citation: Xin G, Wei Z, Ji C, Zheng H, Gu J, Ma L, Huang W, Morris-Natschke SL, Yeh JL, Zhang R, Qin C, Wen L, Xing Z, Cao Y, Xia Q, Li K, Niu H, Lee KH, Huang W. Xanthohumol isolated from Humulus lupulus prevents thrombosis without increased bleeding risk by inhibiting platelet activation and mtDNA release. Free Radic Biol Med. 2017 Jul;108:247-257. doi: 10.1016/j.freeradbiomed.2017.02.018. Epub 2017 Feb 8.
citation: Zhu L, Fan X, Cao C, Li K, Hou W, Ci X. Xanthohumol protect against acetaminophen-induced hepatotoxicity via Nrf2 activation through the AMPK/Akt/GSK3beta pathway. Biomed Pharmacother. 2023 Sep;165:115097. doi: 10.1016/j.biopha.2023.115097. Epub 2023 Jul 3.