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