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

Study Overview
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Brief Summary
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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
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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.

Official Title
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Prevention of Hepatic Encephalopathy by Administration of Rifaximin and Lactulose in Patients With Liver Cirrhosis Undergoing TIPS Placement: a Multi-centre Randomized, Double Blind, Placebo Controlled Trial.

Conditions
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Hepatic Encephalopathy, Cirrhosis, Liver, Portal Hypertension, Liver Diseases, Pathological Processes

Intervention / Treatment
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* Drug: Rifaximin 550 milligram Oral Tablet [XIFAXAN]
* Drug: Placebo oral tablet
* Drug: Lactulose 667 milligram/milliliter Oral Solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Age ≥18 years Confirmed liver cirrhosis as documented by liver biopsy, elastography (e.g. Fibroscan) or combination of usual radiological and biochemical criteria. Signed informed consent Exclusion Criteria: Any absolute contraindications for TIPS placement Use of ciclosporin Life-threatening variceal bleeding with emergency TIPS placement which can not be delayed 72 hours Age > 80 years Non-cirrhotic portal hypertension Portal vein thrombosis (main trunk) HIV Current or recent (<3 months) use of rifaximin Overt neurologic diseases such as Alzheimer's disease, Parkinson's disease Pregnant or breastfeeding women Patients refusing or unable to sign informed consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Rifaximin and lactulose<br>Rifaximin 550 milligram b.i.d. combined with lactulose | Drug: Rifaximin 550 milligram Oral Tablet [XIFAXAN]<br>* Rifaximin 550 milligram b.i.d. 72 hours before TIPS placement till 3 months post-TIPS<br>* Other names: TARGAXAN;Drug: Lactulose 667 milligram/milliliter Oral Solution<br>* Lactulose based on soft stool frequency, 72 hours before TIPS placement till 3 months post-TIPS<br>* Other names: Lactulose syrup;|
| Placebo Comparator: Placebo and lactulose<br>Placebo b.i.d. combined with lactulose | Drug: Placebo oral tablet<br>* Placebo b.i.d. 72 hours before TIPS placement till 3 months post-TIPS<br>* Other names: Placebo;Drug: Lactulose 667 milligram/milliliter Oral Solution<br>* Lactulose based on soft stool frequency, 72 hours before TIPS placement till 3 months post-TIPS<br>* Other names: Lactulose syrup;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| post-TIPS Hepatic Encephalopathy | post-TIPS Hepatic Encephalopathy | First 3 months after TIPS placement | 

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rifaximin, Lactulose, post-TIPS HE, Prevention