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.

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.

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