A Clinical Randomized Controlled Study on the Prevention and Treatment of Drug-refractory Hepatic Encephalopathy After TIPS With Fecal Microbiota Transplantation
Overview
- Phase
- Phase 1
- Status
- Not yet recruiting
- Sponsor
- Air Force Military Medical University, China
- Enrollment
- 40
- Locations
- 1
- Primary Endpoint
- Incidence and severity of treatment-related adverse events (AEs) and serious adverse events (SAEs)
Overview
Brief Summary
This study is a randomized, placebo-controlled, exploratory phase II clinical trial led by Professor Han Gyeong-ho from the Digestive Disease Hospital of Xi'an International Medical Center. The study enrolled 40 patients who had experienced recurrence of hepatic encephalopathy despite treatment with rifaximin and lactulose. These patients were randomly divided 1:1 into the experimental group and the control group. After obtaining informed consent from the patients, fecal microbiota transplantation or placebo control was performed. The fecal microbiota was sourced from the feces of healthy individuals who had a rich composition of the Muribaculaceae, Ruminococcaceae, and Bifidobacteriaceae families and did not contain pathogenic bacteria. The safety and efficacy of the treatment were followed up, and blood and fecal samples were collected for sequencing analysis. The aim was to provide new solutions for patients with hepatic encephalopathy who did not respond to the treatment with rifaximin and lactulose after TIPS surgery; and to explore the impact of microbiota changes and translocation on the recurrence of hepatic encephalopathy after TIPS surgery.
Detailed Description
This study is a single-center, randomized, placebo-controlled, exploratory phase II clinical trial. A total of 40 patients aged 18-75 years who had drug-refractory hepatic encephalopathy after transjugular intrahepatic portosystemic shunt surgery and experienced at least 2 West Haven grade ≥2 hepatic encephalopathy episodes within 6 months of treatment with lactulose and rifaximin were planned to be enrolled: These patients were randomly assigned in a 1:1 ratio to the fecal microbiota transplantation group and the placebo group. Both groups received basic standard treatment: 1200mg/day of rifaximin + 25ml/once of lactulose, twice/day; The FMT group was additionally infused with fecal suspension (100mL/once, twice/day, for 3 consecutive days) through the nasal jejunostomy tube combined with oral enteric-coated freeze-dried fecal capsules (7 capsules each time, for 1 week), while the placebo group was given the same volume of placebo solution and placebo capsules, with the same frequency and duration as the FMT group. All subjects were followed up at 15 days, 1 month, 3 months, and 6 months after transplantation. The primary outcomes were the safety (adverse events, severe adverse events, FMT-related adverse events) and efficacy (hepatic encephalopathy recurrence rate, time to first recurrence, West Haven classification) of FMT; The secondary outcomes were changes in intestinal flora colonization and diversity, liver function, blood ammonia levels, and health-related quality of life (CLDQ scale). Fecal and blood samples were collected at each follow-up time point for multi-omics detection and analysis. Statistical analysis of the trial data was performed using Kaplan-Meier method, Log-rank test, and Cox proportional hazards regression model.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Prevention
- Masking
- Double (Participant, Investigator)
Masking Description
This trial adopts a double-blind design for participants and investigators. FMT preparations (nasojejunal infusion solution + enteric-coated capsules) and matched placebo are identical in appearance, dosage form, administration route, frequency and course. Preparations are coded by independent researchers not involved in trial implementation. All participants, investigators, outcome assessors and statisticians will remain blinded to group allocation. The randomization code will be unblinded only after all clinical data are locked, with an emergency unblinding mechanism for serious adverse events.
Eligibility Criteria
- Ages
- 18 Years to 75 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- •Aged between 18 and 75 years old
- •Patients who have experienced esophageal-gastric variceal bleeding or recurrent refractory ascites and meet the inclusion criteria, and for whom conservative treatment has failed, are planned to undergo elective TIPS surgery
- •Patients with recurrent hepatic encephalopathy (HE) after transjugular intrahepatic portosystemic shunt (TIPS), despite treatment with lactulose and rifaximin (at least 2 episodes of West Haven grade ≥2 HE within 6 months under lactulose and rifaximin intervention)
- •Provided written informed consent from the patient
Exclusion Criteria
- •Malignant tumors of the liver, gastrointestinal tract or other systems
- •Uncontrolled severe active infection (\>grade 2) or sepsis
- •Spontaneous bacterial peritonitis
- •Complicated with severe cardiac, renal or pulmonary insufficiency
- •Other neuropsychiatric diseases, including dementia
- •Budd-Chiari syndrome
- •Alcohol dependence or use of psychotropic drugs (benzodiazepines, opioids, etc.)
- •History of gastrointestinal surgery (e.g., colectomy) within 3 months before enrollment
- •Pregnant or lactating subjects
- •Poor compliance judged by the investigator
Arms & Interventions
Fecal Microbiota Transplantation Group
All the subjects in this arm continued to receive standard medical treatment for hepatic encephalopathy: rifaximin 0.2g per tablet, 2 tablets per dose, 3 times a day, with a total daily dose of 1200mg; lactulose oral solution 25ml per dose, 2 times a day, with the dosage adjusted as needed according to clinical requirements. On the basis of the standard treatment, the subjects received intranasal jejunal tube infusion of fecal suspension (100mL per dose, 2 times a day, for 3 consecutive days), followed by oral enteric-coated freeze-dried fecal capsules (7 capsules per day, for 1 week). The fecal preparation was prepared under sterile conditions. The donor feces used were all subjected to strict screening for infectious diseases and pathogenicity and were rich in Clostridium mucosum, Rumenoccus, and Bifidobacterium.
Intervention: Fecal Microbiota Transplantation (Biological)
Fecal Microbiota Transplantation Group
All the subjects in this arm continued to receive standard medical treatment for hepatic encephalopathy: rifaximin 0.2g per tablet, 2 tablets per dose, 3 times a day, with a total daily dose of 1200mg; lactulose oral solution 25ml per dose, 2 times a day, with the dosage adjusted as needed according to clinical requirements. On the basis of the standard treatment, the subjects received intranasal jejunal tube infusion of fecal suspension (100mL per dose, 2 times a day, for 3 consecutive days), followed by oral enteric-coated freeze-dried fecal capsules (7 capsules per day, for 1 week). The fecal preparation was prepared under sterile conditions. The donor feces used were all subjected to strict screening for infectious diseases and pathogenicity and were rich in Clostridium mucosum, Rumenoccus, and Bifidobacterium.
Intervention: Rifaximin、Lactulose (Drug)
Placebo Control Group
All subjects in this arm will receive the exact same standard medical therapy as the FMT group: rifaximin 0.2g tablets, 2 tablets each time, 3 times daily (total 1200mg per day); lactulose oral solution 25ml each time, twice daily, with dose adjusted according to clinical needs. On top of standard therapy, subjects will receive isovolumetric placebo solution via nasojejunal tube infusion (same frequency and duration as the FMT group), followed by matched oral placebo capsules (same dosage, frequency and duration as the FMT group). Placebo preparations are identical to FMT preparations in appearance, dosage form and administration route.
Intervention: FMT Matched Placebo (Other)
Placebo Control Group
All subjects in this arm will receive the exact same standard medical therapy as the FMT group: rifaximin 0.2g tablets, 2 tablets each time, 3 times daily (total 1200mg per day); lactulose oral solution 25ml each time, twice daily, with dose adjusted according to clinical needs. On top of standard therapy, subjects will receive isovolumetric placebo solution via nasojejunal tube infusion (same frequency and duration as the FMT group), followed by matched oral placebo capsules (same dosage, frequency and duration as the FMT group). Placebo preparations are identical to FMT preparations in appearance, dosage form and administration route.
Intervention: Rifaximin、Lactulose (Drug)
Outcomes
Primary Outcomes
Incidence and severity of treatment-related adverse events (AEs) and serious adverse events (SAEs)
Time Frame: From the date of randomization to the end of 6-month follow-up after intervention
Record the number, incidence, severity (graded by NCI-CTC v3.0 criteria), correlation with trial intervention, and outcome of all AEs, FMT-related AEs and SAEs in subjects from randomization to the end of follow-up. Key monitoring includes gastrointestinal reactions, infection, exacerbation of hepatic encephalopathy and other intervention-related adverse events.
Secondary Outcomes
- The recurrence rate of hepatic encephalopathy fecal microbiota transplantation intervention(From the date of randomization to the end of 6-month follow-up after intervention)
- The changes in health-related quality of life after fecal microbiota transplantation intervention(Baseline, 1 month after intervention, 3 months after intervention, 6 months after intervention)
- The colonization status of the intestinal microbiota(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(Baseline, 15 days after intervention, 1 month after intervention, 3 months after intervention, 6 months after intervention)
Investigators
Guohong Han
Professor
Air Force Military Medical University, China