Prevention of Post-TIPS Hepatic Encephalopathy by Administration of Rifaximin and Lactulose

Phase 4

Recruiting

• Conditions: Hepatic Encephalopathy; Pathological Processes; Cirrhosis, Liver; Portal Hypertension; Liver Diseases
• Interventions: Drug: Rifaximin 550 milligram Oral Tablet [XIFAXAN]; Drug: Placebo oral tablet; Drug: Lactulose 667 milligram/milliliter Oral Solution

• Registration Number: NCT04073290
• Lead Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Brief Summary

Rationale: Hepatic encephalopathy (HE) is a major and common complication in patients with liver cirrhosis. HE can be classified in the extensive range of neurocognitive deterioration as minimal HE (MHE), covert HE (grade I), or overt HE (OHE, grade II-IV). Liver cirrhosis is the most common cause of portal hypertension (PH). Patients who develop complications of PH, like variceal bleeding or refractory ascites, can benefit from a Transjugular Intrahepatic Portosystemic Shunt (TIPS) placement. Unfortunately, post-TIPS HE is a common and often severe complication. Incidence of new onset or worsening of HE after TIPS is approximately 20-45%. Currently there is no strategy to prevent post-TIPS HE.

Detailed Description

Objective: To assess the incidence of post-TIPS OHE within the first three months after prophylactic administration of lactulose and rifaximin versus placebo in patients who undergo Transjugular Intrahepatic Portosystemic Shunt (TIPS) placement.

Study design: A multicentre, randomized, placebo-controlled, double blind study.

Study population: Adult consecutive patients undergoing elective TIPS placement (for refractory ascites or secondary prophylaxis in variceal bleeding) in all Dutch academic centres where TIPS procedures are performed: Amsterdam UMC, location Academic Medical Centre (AMC), Erasmus MC, Leiden University Medical Centre (LUMC), Maastricht University Medical Centre+ (MUMC+), Radboud University Medical Centre (Radboudumc), University Medical Centre Groningen (UMCG), and University Hospitals Leuven (UZ Leuven) in Belgium.

Intervention: Rifaximin 550 milligram (mg) b.i.d. will be prescribed, in combination with a starting dose of 25 milliliter (mL) lactulose b.i.d. and further dependent on the amount of daily bowel movements, with the objective not to exceed more than two soft stools per day. Intervention will start 72 hours before TIPS placement, and will last till three months after TIPS placement. The control group will receive placebo in combination with lactulose (as described above).

Main study parameters/endpoints: Primary endpoint is the development of OHE within three months after TIPS placement determined by the West Haven criteria. Secondary endpoints are 90 day mortality; development of a second episode of OHE within the first three months; development of OHE in the period between three and twelve months after TIPS placement; development of MHE between TIPS placement and twelve months after placement; the increase of the psychometric hepatic encephalopathy score (PHES) and simplified one minute animal naming test (S-ANT1) compared to baseline. Differences in molecular composition of peripheral / portal blood samples at TIPS placement. Furthermore, quality of life will be assessed.

Study Timeline

• Study First Submitted: 2019-08-27
• Study First Submitted QC: 2019-08-27
• Study First Posted: 2019-08-29
• Study Start: 2020-01-21
• Status Verified: 2025-01
• Last Update Submitted: 2025-01-27
• Last Update Posted: 2025-01-28
• Primary Completion: 2026-09-30
• Study Completion: 2026-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 238

Inclusion Criteria

1. Elective TIPS placement for refractory ascites or recurrent variceal bleeding:

   Recurrent tense ascites and one or more of the following criteria:

   i. Not responding to the maximal dose of diuretics (400 milligram spironolactone and 160 milligram furosemide).

   ii. Kidney insufficiency (Creatinine > 135 umol/L) induced by diuretics. iii. Electrolyte disturbances (Sodium < 125 mmol/L, Potassium > 5.5 mmol/L) induced by diuretics.

   iv. Not tolerating higher dose of diuretics (e.g. because of subjective side effects like muscle cramps).

   Recurrent variceal bleeding, not responsive to treatment with endoscopic band ligation and beta-blockers, with a high risk of failure of endoscopic treatment:

   i. Patients with a variceal bleeding and Child-Pugh C (10-13 points) cirrhosis or ii. Patients with a variceal bleeding, Child-Pugh B and an active bleeding during endoscopy

2. Age ≥18 years

3. Confirmed liver cirrhosis as documented by liver biopsy, elastography (e.g. Fibroscan) or combination of usual radiological and biochemical criteria.

4. Signed informed consent

Exclusion Criteria

1. Any absolute contraindications for TIPS placement
2. Use of ciclosporin
3. Life-threatening variceal bleeding with emergency TIPS placement which can not be delayed 72 hours
4. Age > 80 years
5. Non-cirrhotic portal hypertension
6. Portal vein thrombosis (main trunk)
7. HIV
8. Current or recent (<3 months) use of rifaximin
9. Overt neurologic diseases such as Alzheimer's disease, Parkinson's disease
10. Pregnant or breastfeeding women
11. Patients refusing or unable to sign informed consent

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Rifaximin and lactulose	Lactulose 667 milligram/milliliter Oral Solution	Rifaximin 550 milligram b.i.d. combined with lactulose
Rifaximin and lactulose	Rifaximin 550 milligram Oral Tablet [XIFAXAN]	Rifaximin 550 milligram b.i.d. combined with lactulose
Placebo and lactulose	Placebo oral tablet	Placebo b.i.d. combined with lactulose
Placebo and lactulose	Lactulose 667 milligram/milliliter Oral Solution	Placebo b.i.d. combined with lactulose

Primary Outcome Measures

Name	Time	Method
post-TIPS Hepatic Encephalopathy	First 3 months after TIPS placement	post-TIPS Hepatic Encephalopathy

Secondary Outcome Measures

Name	Time	Method
Transplant free survival	One year	Transplant free survival
development of post-TIPS HE between 3-12 months after TIPS placement	3-12 months	development of post-TIPS HE between 3-12 months after TIPS placement
change in Psychometric Hepatic Encephalopathy Score (PHES) compared to baseline	One year	change in total PHES score compared to baseline (range -15 - +5) a lower score is a worse outcome
Mortality	90 days	Mortality
development of a second episode of post-TIPS HE	3 months	development of a second episode of post-TIPS HE
differences in molecular composition of peripheral / portal blood samples	One year	differences in molecular composition of peripheral / portal blood samples at TIPS placement
differences in molecular composition of peripheral blood samples	One year	differences in molecular composition of peripheral blood samples at baseline, compared to day 10 post-TIPS, week 4, week 12, and week 52;
time to development of post-TIPS HE episode(s)	One year	time to development of post-TIPS HE episode(s)
change in one-minute animal naming test compared to baseline	One year	change in one-minute animal naming test compared to baseline

Trial Locations

Locations (6)

University Medical Center Groningen; 🇳🇱 Groningen, Netherlands

Leiden University Medical Center; 🇳🇱 Leiden, Netherlands

Universitaire Ziekenhuizen Leuven; 🇧🇪 Leuven, Belgium

Academic Medical Centre; 🇳🇱 Amsterdam, Netherlands

Erasmus Medical Center; 🇳🇱 Rotterdam, Netherlands

Radboud University; 🇳🇱 Nijmegen, Netherlands