E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
post-TIPS Hepatic Encephalopathy (HE) |
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E.1.1.1 | Medical condition in easily understood language |
Hepatic Encephalopathy after Transjugular Intrahepatic Portosystemic Shunt placement |
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E.1.1.2 | Therapeutic area | Diseases [C] - Symptoms and general pathology [C23] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10019660 |
E.1.2 | Term | Hepatic encephalopathy |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10076204 |
E.1.2 | Term | Minimal hepatic encephalopathy |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10066599 |
E.1.2 | Term | Hepatic encephalopathy prophylaxis |
E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10068826 |
E.1.2 | Term | Transjugular intrahepatic portosystemic shunt |
E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the prophylactic administration of lactulose and rifaximin in patients who undergo Transjugular Intrahepatic Portosystemic Shunt (TIPS) placement, to lower the incidence of post-TIPS over hepatic encephalopathy (OHE) within the first three months. |
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E.2.2 | Secondary objectives of the trial |
1. ninety day mortality; 2. transplant-free survival; 3. the development of a second episode of OHE within the first three months after TIPS placement; 4. the development of OHE between three and twelve months after TIPS placement; 5. the change in PHES and S-ANT1 test during the study: at time-points week 4, week 12 and week 52, compared to baseline; 6. differences in molecular composition of peripheral / portal blood samples at TIPS placement; 7. differences in molecular composition of peripheral blood samples at baseline, compared to day 0, week 4, week 12, and week 52; 8. quality of life; 9. costs and cost-effectiveness. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Substudy 1, protocol version 1.0, date 13 december 2018: Title: The evolution of microbiota composition and microbiota-host interaction after TIPS placement in relation to post-TIPS HE and outcome Primary objective of this ancillary study is to assess the effect of TIPS placement on microbiota-host interaction based on the following assessments at baseline, day 0, month 3 and month 12: - 16s rRNA based analysis of microbiota in stool - 16s rRNA based analysis of microbiota in saliva - Circulating biomarkers for inflammatory, circulatory and endothelial function.
Secondary objectives are: - to assess the relationship between post-TIPS hepatic encephalopathy and microbiota composition. - to assess the relationship between post-TIPS hepatic encephalopathy and inflammatory, circulatory and endothelial function respectively. - to assess the relationship between post-TIPS acute decompensation/ACLF or mortality at short (3 months) and long term (< 12 months) and microbiota composition. - to assess the relationship between post-TIPS acute decompensation/ACLF or mortality at short (3 months) and long term (< 12 months) and inflammatory, circulatory and endothelial function respectively.
Substudy 2, protocol version 1.0, date 13 december 2018: Characterisation of monocyte activation status and cytokine production in decompensated cirrhosis, alcoholic hepatitis and acute on chronic liver failure. Objectives: • To compare the activation status, immunological and metabolic function of circulating monocytes/macrophages obtained from patients with alcoholic liver cirrhosis (ALD). • Identify the levels of bacterial products, in the portal and systemic blood from patients with ALD. • Identify the nature and levels of inflammatory cytokines reaching the liver from the gut in patients with decompensated liver disease undergoing TIPS for intractable ascites • To determine the pre and post TIPS immunological factors that may be predictive of encephalopathy following TIPS placement. • To determine the activation status, cytokines responses, immunological- and metabolic function by circulating monocytes present in the peripheral blood of patients admitted with acute alcoholic hepatitis and acute- on- chronic liver failure and how these individual responses may correlate with survival. • To follow up patients longitudinally and identify a set of parameters and read-outs that can predict patient outcome. |
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E.3 | Principal 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 (400mg spironolactone and 160mg 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/or 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 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 |
1. Electieve TIPS plaatsing voor therapie refractaire ascites of therapie refractaire varicesbloeding: • Refractaire ascites en een of meer van de volgende criteria: i. Niet reagerend op de maximale dosering diuretica (400mg spironolacton en 160mg furosemide). ii. Nierinsufficientie (Kreatinine > 135 umol/L) geinduceerd door diuretica. iii. Electrolyten verstoren (Natrium < 125 mmol/L, Kalium > 5.5 mmol/L) geinduceerd door diuretica. iv. Niet tolereren van hoge dosering diuretica (b.v. door subjectieve klachten van spierkrampen). • (Therapie refractaire) varices bloedingen, niet reagerend op behandeling met endoscopische band ligatie en/of beta-blokkers, met een hoog risico op falen van endoscopische behandeling: i. Patienten met varices bloeding en Child-Pugh C (10-13 punten) cirrose ii. Patienten met varices bloeding, Child-Pugh B en een actieve bloeding tijdens endoscopie 2. Leeftijd ≥ 18 jaar 3. Bevestigde levercirrose: gedocumenteerd leverbiopt, Fibroscan of een combinatie van de gebruikelijke radiologische en biochemsiche criteria. 4. Getekend informed consent formulier |
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E.4 | Principal exclusion criteria |
1. Any absolute contraindications for TIPS placement: a. History of hepatic encephalopathy grade II-IV without precipitating factor b. Heart failure NYHA ≥ grade 3 c. Hepatocellular carcinoma (multifocal or large or centrally located) d. Systemic infection / sepsis e. Severe pulmonary hypertension f. Unrelieved bile duct obstruction g. Technically not feasible h. Poor liver function (MELD score > 20) 2. Use of ciclosporin 3. Life-threating variceal bleeding with emergency TIPS placement 4. Age > 80 years 5. Non-cirrhotic portal hypertension 6. Portal vein thrombosis 7. Current or recent (<3 months) use of rifaximin 8. Overt neurologic diseases such as Alzheimer’s disease, Parkinson’s disease 9. HIV 10. Pregnant or breastfeeding women 11. Patients refusing or unable to sign informed consent |
1. Een absolute contraindicatie voor TIPS plaatsing: a. Medische voorgeschiedenis van HE graad II-IV zonder uitlokkende factor b. Hartfalen NYHA ≥ graad 3 c. Hepatocellulair carcinoom (multifocaal of groot of centraal gelegen) d. Systemische infectie / sepsis e. Ernstige pulmonale hypertensie f. Onopgeloste galweg obstructie g. Technische niet haalbaar h. Slechte leverfunctie (MELD score > 20) 2. Gebruik van cyclosporine 3. Levensbedreigende varicesbloeding waarbij direct TIPS plaatsing nodig is 4. Leeftijd > 80 5. Non-cirrotische portale hypertensie 6. Vena portae trombose 7. Huidig of recent (<3 maanden) gebruik van rifaximine 8. Ernstig neurlogische ziekte zoals Alzheimer of Parkinson 9. HIV 10. Zwanger of borstvoedending gevende vrouw 11. Patienten die weigeren informed consent te tekenen |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary endpoint is the development of OHE within three months after TIPS placement determined by the West Haven criteria. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Three months after TIPS placement. |
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E.5.2 | Secondary end point(s) |
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; time to development of OHE or MHE episodes; the increase of the PHES, S-ANT1 score and LFI compared to baseline. Difference in the composition of portal blood samples, drawn at TIPS placement. Difference in the composition of peripheral blood samples, drawn at different study timepoints. Furthermore, quality of life will be assessed by the Liver Disease Symptom Index 2.0 (LDSI 2.0) and EQ-5D-5L questionnaires. Costs will include costs of health care, productivity loss due to sick leave from work and out-of-pocket expenses. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Quality of life is measured at baseline, three and twelve months after TIPS placement. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | No |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 8 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |