Fecal Microbiota Transplantation for the Treatment of Refractory Hepatic Encephalopathy After TIPS Surgery

Официальное название

A Prospective Exploratory Study on Fecal Microbiota Transplantation for the Treatment of Refractory Hepatic Encephalopathy After TIPS Surgery

Обзор

This is a single-center, prospective, open-label, parallel-group exploratory clinical study designed to evaluate the safety and preliminary efficacy of fecal microbiota transplantation combined with standard medical therapy in patients with refractory overt hepatic encephalopathy after transjugular intrahepatic portosystemic shunt. The study also aims to explore whether adjunctive prebiotic supplementation may improve clinical outcomes and support gut microbiota reconstruction after fecal microbiota transplantation. A total of 26 participants with recurrent overt hepatic encephalopathy after TIPS despite standard therapy with rifaximin and lactulose will be enrolled. All participants will continue to receive standard medical therapy, including rifaximin and lactulose. During an episode of overt hepatic encephalopathy, all participants will receive fecal microbiota transplantation via a nasojejunal tube at a dose of 100 mL per administration, twice daily, for 3 consecutive days. Participants will be assigned in a 1:1 ratio to either the fecal microbiota transplantation group or the fecal microbiota transplantation plus prebiotic group. Participants in the combination group will receive dietary fiber prebiotic supplementation at 24 g/day for 4 weeks in addition to the same fecal microbiota transplantation and standard medical therapy. Participants will be followed for up to 6 months. The primary efficacy assessment will focus on recurrence of hepatic encephalopathy, including recurrence rate, time to first recurrence, episode grade, and duration. Secondary assessments will include time to reversal of hepatic encephalopathy, West Haven grade, blood ammonia, liver and kidney function, inflammatory markers, liver function scores, neurocognitive function, and changes in gut microbiota composition. Safety assessments will include adverse events, fecal microbiota transplantation-related adverse events, infection, worsening hepatic encephalopathy, hospitalization, and serious adverse events. This study is expected to provide preliminary clinical evidence for a microbiota-based therapeutic strategy in patients with refractory overt hepatic encephalopathy after TIPS.

Подробное описание

Hepatic encephalopathy is one of the most common and clinically significant complications after transjugular intrahepatic portosystemic shunt. After TIPS, portosystemic shunting may increase the systemic exposure to gut-derived neurotoxins and inflammatory mediators, thereby increasing the risk of overt hepatic encephalopathy. Although lactulose and rifaximin are widely used as standard medical therapy, some patients continue to experience recurrent overt hepatic encephalopathy despite adequate treatment. For patients with refractory overt hepatic encephalopathy after TIPS, current therapeutic options remain limited, particularly in terms of rapid recovery of consciousness, prevention of recurrence, and restoration of gut microbial homeostasis.

Fecal microbiota transplantation may provide a microbiota-based therapeutic approach by reshaping the intestinal microbial ecosystem, modulating gut-derived toxin production, improving intestinal barrier and metabolic function, and regulating the gut-liver-brain axis. Previous studies have suggested that fecal microbiota transplantation may be safe and potentially effective in patients with cirrhosis-related hepatic encephalopathy. However, clinical evidence remains limited in patients with refractory overt hepatic encephalopathy specifically occurring after TIPS. In addition, prebiotics may support the growth and engraftment of beneficial bacterial taxa after fecal microbiota transplantation by providing fermentable dietary substrates. Therefore, this study is designed to evaluate the safety and preliminary efficacy of fecal microbiota transplantation combined with standard therapy in patients with refractory overt hepatic encephalopathy after TIPS, and to compare the clinical and microbiome-related effects of fecal microbiota transplantation with or without adjunctive prebiotic supplementation.

This is a single-center, prospective, open-label, parallel-group exploratory clinical study. A total of 26 eligible participants with refractory overt hepatic encephalopathy after TIPS will be enrolled. Eligible participants will be adults aged 18 to 75 years who have successfully undergone covered-stent TIPS and have experienced at least two episodes of overt hepatic encephalopathy with West Haven grade 2 or higher within 6 months despite treatment with rifaximin and lactulose. Participants must also be suitable for fecal microbiota transplantation via a nasojejunal tube and able to tolerate tube placement and subsequent infusion procedures. Key exclusion criteria include active major gastrointestinal bleeding or perforation, severely impaired intestinal barrier function, congenital or acquired immunodeficiency, recent high-risk immunosuppressive or cytotoxic therapy, hepatic or gastrointestinal malignancy, spontaneous bacterial peritonitis, Budd-Chiari syndrome, severe cardiac, renal, or pulmonary dysfunction, unstable vital signs, recent gastrointestinal surgery, planned liver transplantation within 6 months, recent fecal microbiota transplantation, alcohol dependence, use of medications that may affect neuropsychiatric status, other neuropsychiatric disorders, pregnancy or lactation, and poor compliance as judged by the investigator.

All enrolled participants will continue to receive standard medical therapy. Standard therapy consists of rifaximin 0.4 g three times daily, with a total daily dose of 1200 mg, and lactulose 25 mL twice daily, adjusted as clinically needed. During an episode of overt hepatic encephalopathy, all participants will receive fecal microbiota transplantation via a nasojejunal tube. The fecal microbiota suspension will be administered at 100 mL per infusion, twice daily, for 3 consecutive days. The fecal microbiota product will be prepared from rigorously screened healthy donors under standardized conditions, with controlled storage and traceability. Participants will be assigned in a 1:1 ratio to the fecal microbiota transplantation group or the fecal microbiota transplantation plus prebiotic group, with 13 participants in each group. Participants in the combination group will receive additional dietary fiber prebiotic supplementation at a total dose of 24 g/day, administered as 12 g twice daily, starting on the day of fecal microbiota transplantation and continuing for 4 weeks.

Efficacy and safety will be systematically assessed during treatment and follow-up. Clinical assessments will include vital signs, mental status, West Haven grade, time to reversal of hepatic encephalopathy, recurrence of hepatic encephalopathy, hospitalization, and adverse events. Laboratory assessments will include complete blood count, liver function, renal function, coagulation function, plasma ammonia, hepatitis B virus DNA when applicable, alpha-fetoprotein, endotoxin, C-reactive protein, and interleukin-6. Liver disease severity will be assessed using Child-Pugh and MELD scores. Minimal hepatic encephalopathy testing and neurocognitive assessments will be performed when clinically feasible.

The primary efficacy endpoint is recurrence of hepatic encephalopathy, including recurrence rate, time to first recurrence, episode grade, episode duration, and the time from fecal microbiota transplantation to the first recurrence of hepatic encephalopathy. Secondary efficacy endpoints include changes in blood ammonia, liver function, renal function, inflammatory markers, liver function scores, psychological or neurocognitive test results, and gut microbiota diversity and taxonomic composition before and after fecal microbiota transplantation. Safety endpoints include overall adverse events, fecal microbiota transplantation-related adverse events, and serious adverse events, with particular attention to gastrointestinal symptoms, infection, worsening hepatic encephalopathy, hospitalization, septic shock, and death.

Participants will be followed at baseline before fecal microbiota transplantation, day 0 after completion of transplantation, day 15, month 1, month 3, and month 6. Additional assessments will be performed when hepatic encephalopathy occurs. At each scheduled time point, 5 mL of peripheral venous blood and 5 g of stool will be collected for laboratory testing and gut microbiota analysis. These data will be used to explore associations between microbial changes, clinical improvement, recurrence of hepatic encephalopathy, and safety outcomes.

Statistical analyses will be performed using the intention-to-treat principle. Clinical variables will be summarized using appropriate descriptive statistics and compared between groups when applicable. Time-dependent outcomes, including time to first recurrence and recurrence-free survival, will be analyzed using the Kaplan-Meier method and the Log-rank test. Competing risk models may be used to account for death or liver transplantation as competing events. Cox proportional hazards regression models will be used to explore factors associated with clinical outcomes. Microbiome data will be analyzed using diversity analysis, donor-recipient similarity assessment, changes in dominant bacterial taxa, and correlation or multivariable models to explore the relationship between gut microbiota dynamics and clinical outcomes.

Вмешательства

• Биопрепарат Fecal Microbiota Transplantation
  Fecal microbiota transplantation is used to reconstruct gut microbiota structure, regulate intestinal microecological homeostasis, improve intestinal barrier function, reduce systemic endotoxin load and inflammatory level, for the prevention and treatment of refractory hepatic encephalopathy after TIPS. The preparation is made from stool of qualified screened donors, processed under sterile conditions.
• Препарат Rifaximin、Lactulose
  Rifaximin is a non-absorbable oral rifamycin antibiotic, used as standard medical therapy for hepatic encephalopathy, to reduce intestinal urease-producing bacteria and intestinal ammonia production.Lactulose is a synthetic disaccharide laxative, used as first-line standard medical therapy for hepatic encephalopathy, to acidify the intestinal lumen, reduce ammonia production and promote ammonia excretion.
• Пищевая добавка Dietary Fiber Prebiotic
  Participants assigned to the FMT plus prebiotic group will receive dietary fiber prebiotic supplementation in addition to fecal microbiota transplantation and standard medical therapy. The prebiotic will be administered at a total dose of 24 g per day, given as 12 g twice daily, starting on the day of fecal microbiota transplantation and continuing for four weeks. Standard medical therapy with rifaximin and lactulose will be continued during the study period.

Первичные конечные точки

• Incidence and severity of treatment-related adverse events (AEs) and serious adverse events (SAEs) [Срок оценки: From the date of randomization to the end of 6-month follow-up after intervention]

Вторичные конечные точки (4)

• Reversal time of hepatic encephalopathy [Срок оценки: Throughout the entire period from the end of the intervention to 6 months after the intervention]
• Recurrent rate of hepatic encephalopathy [Срок оценки: Throughout the entire period from the end of the intervention to 6 months after the intervention]
• The colonization status of the intestinal microbiota [Срок оценки: Baseline, 15 days after intervention, 1 month after intervention, 3 months after intervention, 6 months after intervention]
• Changes in the α diversity of the intestinal microbiota [Срок оценки: Baseline, 15 days after intervention, 1 month after intervention, 3 months after intervention, 6 months after intervention]

Критерии участия

Критерии включения

• Age: 18 - 75 years old, both genders are eligible
• Successful implementation of covered stent TIPS
• Those who experienced recurrence of hepatic encephalopathy after TIPS surgery and still used lactulose and rifaximin (within 6 months after intervention with rifaximin and lactulose, West Haven grade ≥ 2 hepatic encephalopathy occurred at least 2 times)
• Meet the conditions for receiving fecal microbiota transplantation through nasogastric tube (no severe anatomical abnormalities in the upper digestive tract; basic intestinal motility is normal; can tolerate the insertion of nasogastric tube and the subsequent infusion process)
• Obtain the patient's written informed consent

Критерии исключения

• Patients with active gastrointestinal bleeding or perforation accompanied by severe damage to the intestinal barrier due to various reasons
• Patients with congenital or acquired immunodeficiency diseases, those who have received high-risk immunosuppressive or cytotoxic drug treatment within the recent 3 months, and those with severe immunosuppression (neutrophil count < 1.5×10⁶ cells/L; CD4+ T cell count < 2.0×10⁵ cells/L)
• Patients with malignant tumors of the liver or gastrointestinal tract, patients with spontaneous bacterial peritonitis, and patients with Budd-Chiari syndrome
• Patients with severe heart, kidney, or lung dysfunction (NYHA III-IV grade or unstable heart failure; eGFR < 30 ml/min/1.73m² or requiring dialysis; respiratory failure or requiring long-term oxygen therapy)
• Unstable vital signs (body temperature, heart rate, blood pressure, breathing)
• History of gastrointestinal surgery within the past 3 months, such as colon resection
• Patients planning to undergo liver transplantation within 6 months
• Patients who have undergone FMT within the past 3 months
• Alcohol dependence or use of psychotropic drugs (benzodiazepines, opioids, etc.)
• Other neurological and psychiatric disorders, including dementia, Parkinson's disease, and post-stroke sequelae
• Pregnant or lactating subjects
• Subjects considered to have poor compliance by the investigator

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

Здоровые добровольцы: Да

Дизайн исследования

Распределение

Нерандомизированное

Модель

Параллельные группы

Маскирование

Простое слепое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• Xi'an International Medical Center Hospital — Сиань

Публикации

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• Bajaj JS, Kassam Z, Fagan A, Gavis EA, Liu E, Cox IJ, Kheradman R, Heuman D, Wang J, Gurry T, Williams R, Sikaroodi M, Fuchs M, Alm E, John B, Thacker LR, Riva A, Smith M, Taylor-Robinson SD, Gillevet PM. Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: A randomized clinical trial. Hepatology. 2017 Dec;66(6):1727-1738. doi: 10.1002/hep.29306. Epub 2017 Oct 3 PMID 28586116
• Bajaj JS, Salzman NH, Acharya C, Sterling RK, White MB, Gavis EA, Fagan A, Hayward M, Holtz ML, Matherly S, Lee H, Osman M, Siddiqui MS, Fuchs M, Puri P, Sikaroodi M, Gillevet PM. Fecal Microbial Transplant Capsules Are Safe in Hepatic Encephalopathy: A Phase 1, Randomized, Placebo-Controlled Trial. Hepatology. 2019 Nov;70(5):1690-1703. doi: 10.1002/hep.30690. Epub 2019 Jun 18. PMID 31038755
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• Duttagupta S, Messaoudene M, Hunter S, Desilets A, Jamal R, Mihalcioiu C, Belkaid W, Marcoux N, Fidelle M, Suissa D, Ponce M, Geiger M, Malo J, Piccinno G, Puncochar M, Filin A, Heidrich V, Rusu D, Mbaye B, Durand S, Ben Aissa I, Puller V, de Lahondes R, Blais N, Tehfe M, Owen S, Belanger K, Parvathy SN, Shieh B, Raphael J, Lenehan J, Breadner D, Rothenstein J, Rozza N, Maillou J, Nili S, Prifti D PMID 41606121
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• Quan X, Li Y, Wu H. Reply to "Probiotics for Hepatic Encephalopathy Prevention After TIPS: Still an Open Question". Liver Int. 2025 Nov;45(11):e70383. doi: 10.1111/liv.70383. No abstract available. PMID 41047753

Идентификаторы

NCT: NCT07683936 · TIPS-HE-FMT002

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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