Cirrhosis, Liver, Hepatic Encephalopathy, Liver Diseases, Pathological Processes, Portal Hypertension
Conditions
Keywords
Rifaximin, Lactulose, post-TIPS HE, Prevention
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.
Interventions
Rifaximin 550 milligram b.i.d. 72 hours before TIPS placement till 3 months post-TIPS
DRUGPlacebo oral tablet
Placebo b.i.d. 72 hours before TIPS placement till 3 months post-TIPS
DRUGLactulose 667 milligram/milliliter Oral Solution
Lactulose based on soft stool frequency, 72 hours before TIPS placement till 3 months post-TIPS
Sponsors
Erasmus Medical Center
Leiden University Medical Center
Maastricht University Medical Center
Radboud University Medical Center
University Medical Center Groningen
Universitaire Ziekenhuizen KU Leuven
Norgine
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| post-TIPS Hepatic Encephalopathy | First 3 months after TIPS placement | post-TIPS Hepatic Encephalopathy |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| development of a second episode of post-TIPS HE | 3 months | development of a second episode of post-TIPS HE |
| change in one-minute animal naming test compared to baseline | One year | change in one-minute animal naming test compared to baseline |
| 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; |
| Mortality | 90 days | Mortality |
| Transplant free survival | One year | Transplant free survival |
| time to development of post-TIPS HE episode(s) | One year | time to development of post-TIPS HE episode(s) |
| 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 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Cost-effectiveness | One year | Cost-effectiveness, measured by a combined questionnaire, based on institute for Medical Technology Assessment (iMTA) Productivity Cost Questionnaire (iPCQ)/Medical Consumption Questionnaire (iMCQ) |
| Disease rrelated Quality of life | One year | Health related Quality of life, Liver Disease Symptom Index (LDSI) 2.0 questionnaire. |
| Health related Quality of life | One year | Health related Quality of life, measured by EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) questionnaire |
Countries
Belgium, Netherlands
Contacts
Primary ContactKoos de Wit, MD
Outcome results
None listed