UDCA to Prevent Post-TIPS Hepatic Encephalopathy

Официальное название

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Ursodeoxycholic Acid Plus Lactulose vs Lactulose Alone for the Prevention of Overt Hepatic Encephalopathy After TIPS Placement

Обзор

Hepatic encephalopathy (HE) commonly occurs after transjugular intrahepatic portosystemic shunt (TIPS). Ursodeoxycholic acid (UDCA) has been reported to alleviate neurodegenerative disease recently. This open-label multicenter randomized controlled trial tests whether adding UDCA (13-15 mg/kg/day) to standard lactulose prophylaxis reduces the incidence of overt HE (OHE; West Haven grade II-IV) after TIPS, compared with lactulose alone. The regimen starts within 72 hours before TIPS and continues for 3 months. The trial aims to evaluate the effect of UDCA in reducing the incidence of post-TIPS OHE.

Подробное описание

Post-TIPS OHE occurs in 35-50% of patients and worsens quality of life and resource use. Existing guidance consistently recommends lactulose as the backbone therapy for HE and for secondary prophylaxis, titrated to 2-3 soft stools/day; however, evidence for primary prophylaxis after TIPS has been limited and heterogeneous, and consensus varies across documents. Hydrophilic bile acids, especially ursodeoxycholic acid (UDCA), have demonstrated important anti-apoptotic and neuroprotective activities in clinical practice. Published experimental and clinical evidence suggests its potential therapeutic use as a disease-modifier in neurodegenerative and metabolic brain diseases. This trial evaluates whether bile-acid modulation with UDCA at standard hepatology dosing (13-15 mg/kg/day) combined with lactulose reduces early post-TIPS OHE. The protocol uses stratified randomization, prespecified outcome adjudication (West Haven), and intention-to-treat analysis. Key secondary endpoints include mortality, transplant-free survival, minimal HE tests (PHES, Stroop test), frailty, quality of life, and bile-acid/metabolomic profiling in optional sub-studies.

Вмешательства

• Препарат Ursodeoxycholic Acid (UDCA)
  13-15 mg/kg/day orally, in divided doses (BID), starting ≤72 hours before TIPS and continued for 3 months.
• Препарат Lactulose
  Syrup 25 mL BID, initiated after TIPS procedure, titrated to 1-2 soft stools/day, with dose reduction if diarrhea occurs.

Первичные конечные точки

• Incidence of Overt Hepatic Encephalopathy (OHE) within 3 Months After TIPS [Срок оценки: From TIPS procedure (Day 0) to 3 months post-TIPS (Day 90).]

Критерии участия

Критерии включения

• Age 18-80 years.
• Confirmed cirrhosis (biopsy, elastography, or standard radiologic/biochemical criteria).
• Elective TIPS for (a) refractory/recurrent ascites and/or (b) recurrent variceal bleeding not responsive to treatment with endoscopic band ligation and beta-blockers.
• Preemptive TIPS for patients with variceal bleeding and Child-Pugh C (10-13 points), patients with Child-Pugh B and active bleeding during endoscopy, or patients with hepatic venous pressure gradient (HVPG) ≥ 20 mmHg.
• Ability to start study drug within 72 hours before TIPS.
• Signed informed consent.

Критерии исключения

• Contraindications to TIPS (e.g., severe heart failure ≥NYHA III, severe pulmonary hypertension, uncontrolled sepsis, advanced HCC at risk with TIPS, unrelieved biliary obstruction, Child-Pugh score >13, main-trunk PVT if not recanalizable, technical infeasibility).
• Prior OHE grade II-IV without precipitating factor; overt neurological disease affecting cognition (e.g., Parkinson's, Alzheimer's).
• Current or planned ursodeoxycholic acid (UDCA) therapy for an approved indication (e.g., primary biliary cholangitis), or UDCA use within the prior 3 months.
• Current/recent rifaximin use (<3 months) or strong UDCA contraindication/hypersensitivity.
• Salvage TIPS.
• Non-cirrhotic portal hypertension.
• Pregnancy/lactation.
• Any condition that, in investigators' judgment, precludes safe participation.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Профилактика

Центры проведения

Китай · 1 центр

• West China Hospital, Sichuan University — Чэнду

Публикации

• Maharshi S, Sharma BC. Prophylaxis of hepatic encephalopathy: current and future drug targets. Hepatol Int. 2024 Aug;18(4):1096-1109. doi: 10.1007/s12072-024-10647-9. Epub 2024 Mar 16. PMID 38492132
• Kronsten VT, Paintsil EK, Rodrigues S, Seager MJ, Bernal W, Shawcross DL. Hepatic Encephalopathy: When Lactulose and Rifaximin Are Not Working. Gastroenterology. 2025 Jun;168(6):1076-1084.e1. doi: 10.1053/j.gastro.2025.01.010. Epub 2025 Jan 24. No abstract available. PMID 39864468
• Djernes L, Vilstrup H, Ott P, Eriksen PL. Blood ammonia concentration measurement - effects of sampling site and cirrhosis during induced hyperammonaemia. Metab Brain Dis. 2024 Nov 20;40(1):21. doi: 10.1007/s11011-024-01442-4. PMID 39565434
• Shawcross DL, Thabut D, Amodio P. Ammonia - an enduring foe - What evaluating whole body ammonia metabolism can teach us about cirrhosis and therapies treating hepatic encephalopathy. J Hepatol. 2023 Aug;79(2):266-268. doi: 10.1016/j.jhep.2023.04.039. Epub 2023 May 12. No abstract available. PMID 37178732
• Wang X, Luo X, Yang L. Achieving an effective pressure reduction after TIPS: The need for a new target. J Hepatol. 2021 Jul;75(1):246-248. doi: 10.1016/j.jhep.2021.02.010. Epub 2021 Feb 20. No abstract available. PMID 33621635
• Wang X, Liu G, Wu J, Xiao X, Yan Y, Guo Y, Yang J, Li X, He Y, Yang L, Luo X. Small-Diameter Transjugular Intrahepatic Portosystemic Shunt versus Endoscopic Variceal Ligation Plus Propranolol for Variceal Rebleeding in Advanced Cirrhosis. Radiology. 2023 Aug;308(2):e223201. doi: 10.1148/radiol.223201. PMID 37606572
• Xiang Y, Tie J, Wang G, Zhuge Y, Wu H, Zhu X, Xue H, Liu S, Yang L, Xu J, Zhang F, Zhang M, Wei B, Li P, Wang Z, Wu W, Chen C, Yang S, Han Y, Tang C, Qi X, Zhang C. Post-TIPS Overt Hepatic Encephalopathy Increases Long-Term but Not Short-Term Mortality in Cirrhotic Patients With Variceal Bleeding: A Large-Scale, Multicenter Real-World Study. Aliment Pharmacol Ther. 2025 Apr;61(7):1183-1196. doi: 1 PMID 39962750
• Liu J, Ma J, Yang C, Chen M, Shi Q, Zhou C, Huang S, Chen Y, Wang Y, Li T, Xiong B. Sarcopenia in Patients with Cirrhosis after Transjugular Intrahepatic Portosystemic Shunt Placement. Radiology. 2022 Jun;303(3):711-719. doi: 10.1148/radiol.211172. Epub 2022 Mar 15. PMID 35289658

Идентификаторы

NCT: NCT07273734 · THE001

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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