Title: Randomised controlled trial of EArly transjugular intrahepatiC porTosystemic stent-shunt in Acute Variceal Bleeding (REACT-AVB)
Funder: Department of Health and Social Care

Abstract: THE CHALLENGE_x000D_ _x000D_ Liver disease is the fifth largest cause of death in the UK. 30,000 – 60,000 people are at risk of, or already have, cirrhosis (scarring of the liver). Over the past decade, the number of 35-55 year olds who have developed cirrhosis has increased fivefold. _x000D_ _x000D_ Cirrhosis can lead to varices (abnormally enlarged veins) developing in the lower gullet (food pipe) or stomach. There’s a 1 in 20 chance of varices bleeding, which can result in death in at least 1 in 7 and in survivors, further bleeding is common. In England 2000 people a year enter hospital with this bleeding. We must therefore offer the best treatment to improve survival by preventing further bleeding. _x000D_ _x000D_ We check for these varices with a device called an endoscopy (a bendy tube incorporating a light and tiny video camera). _x000D_ _x000D_ CURRENT TREATMENTS_x000D_ _x000D_ The current accepted treatment for patients who bleed from varices is known as standard of care (SOC) as follows:_x000D_ _x000D_ 1. Endoscopic treatment_x000D_ _x000D_ During an endoscopy we can:_x000D_ _x000D_ a) tie off an enlarged vein with a rubber ring (variceal banding) or; _x000D_ b) inject a drug, with a needle, directly into the swollen vein, in order to cause that vein to clot, and hence stop bleeding_x000D_ _x000D_ We need to do this every few weeks or months. _x000D_ _x000D_ 2. Medication_x000D_ _x000D_ We may use antibiotics as well as other drugs. Once a patient is stable they are offered drugs which slow down the heart and lower pressure in the enlarged veins, which reduce risk of further bleeding. _x000D_ _x000D_ OUR STUDY – BACKGROUND_x000D_ _x000D_ For some patients we use a device called a Transjugular intrahepatic portosystemic stent-shunt (TIPSS). TIPSS involves placing a special metal tube inside the liver using a wire passed through a vein in the neck and through the liver._x000D_ _x000D_ We can use TIPSS for acute variceal bleeding :_x000D_ a) as an emergency to stop bleeding where SOC has not worked;_x000D_ b) for patients at high risk of bleeding again after satisfactory stabilisation with SOC. We call this “early” TIPSS. _x000D_ _x000D_ _x000D_ OUR STUDY ON EARLY TIPSS – THE PLAN_x000D_ _x000D_ There are only a few clinical trials of early TIPSS with small number of patients. Their results aren’t clear as to which patients benefit from early TIPSS and whether it actually works. Current guidelines recommend further research. Nobody so far has compared early TIPSS with SOC in a large clinical trial and obtained clear results. _x000D_ _x000D_ Our team has much experience of clinical trials with people with liver disease. The team includes two patient collaborators, and a Trustee of Liver4Life (charity). We will involve them and other public contributors regularly in all parts of the research. _x000D_ _x000D_ We want to do a trial to compare early TIPSS with SOC in acute variceal bleeding to see if early TIPSS is better than SOC in improving survival of patients. Patients will get early TIPSS or SOC at random. _x000D_ _x000D_ The trial will seek to recruit just under 300 patients nationally over 4 years. It includes a 12-month pilot study to address any problems early. We will also compare cost-effectiveness, and quality of life for the patients for both treatments. _x000D_ _x000D_ If we conclude that early TIPSS is more effective in terms of survival, cost, and quality of life than SOC, this could lead to a major change in clinical practice.

Lay abstract: Research question:_x000D_ Does early transjugular intrahepatic portosystemic stent-shunt (TIPSS) within 4 days of diagnostic endoscopy result in improved transplant free patient survival when compared with standard of care?_x000D_ _x000D_ Design: _x000D_ This is a pragmatic multicentre randomised controlled open-label two arm superiority parallel group trial._x000D_ _x000D_ Primary outcome:_x000D_ Transplant free survival at one year_x000D_ _x000D_ Secondary outcomes: _x000D_ 1. Transplant free survival at 6 weeks (from randomisation):_x000D_ 2. Rebleeding (from randomisation)_x000D_ a. Early (within 6 weeks)_x000D_ b. Late (6 weeks to 1 year)_x000D_ 3. Adverse events related to treatment (up to 12 months after randomisation):_x000D_ 4. Other complications of cirrhosis: _x000D_ a. New onset ascites _x000D_ b. New onset encephalopathy _x000D_ c. Spontaneous bacterial peritonitis_x000D_ d. Hepatocellular carcinoma_x000D_ 5. Child-Pugh score at 6 and 12 months._x000D_ 6. MELD score at 6 and 12 months. _x000D_ 7. Health-related quality of life (EQ-5D-5L) at 6 and 12 months._x000D_ 8. Use of healthcare resources, costs and cost-effectiveness based on cost per Quality-Adjusted Life-Year (QALY) estimated using the EQ-5D-5L and cost per death avoided at one year, and modelled cost per QALY over patient lifetime._x000D_ 9. Use of alternative therapies (including diuretics and non-selective beta-blockers) _x000D_ _x000D_ Setting: _x000D_ Acute NHS Trusts and Health Boards in the UK that admit and manage patients with acute variceal bleeding. We propose a minimum of 30 sites._x000D_ _x000D_ Target population: _x000D_ Patient with liver cirrhosis presenting with acute variceal bleeding which has been controlled by current therapy as recommended in the BSG guidelines.(3) _x000D_ _x000D_ Inclusion criteria:_x000D_ 1. Liver cirrhosis as defined clinically, radiologically (USS and transient elastography) or on histology. _x000D_ 2. Acute variceal bleed (oesophageal or gastric) with haemostasis following initial endoscopic therapy._x000D_ 3. Child-Pugh score 7-13._x000D_ 4. Age >= 18_x000D_ _x000D_ Exclusion Criteria:_x000D_ 1. Failure to control acute bleeding (as per Baveno 6 criteria)(5) prior to randomisation_x000D_ 2. Previous portosystemic shunt or TIPSS_x000D_ 3. Known occlusive portal vein thrombosis precluding TIPSS_x000D_ 4. Active cancer including hepatocellular carcinoma affecting 1 year survival _x000D_ 5. Contraindication to non-selective beta blockers such as asthma._x000D_ 6. Clinically significant encephalopathy causing recurrent hospital admissions_x000D_ 7. Pregnant or lactating women._x000D_ 8. Evidence of heart failure refractory to treatment._x000D_ 9. Severe active septicaemia. _x000D_ _x000D_ Health technologies: _x000D_ 1. Early transjugular intrahepatic portosystemic stent-shunt (TIPSS) within 4 days of diagnostic endoscopy._x000D_ 2. Endoscopic therapy and non-selective beta-blocker (preferably carvedilol 12.5mg/24h)._x000D_ _x000D_ Sample size:_x000D_ 294 participants (1:1 randomisation) required to show improved transplant free survival from 60% to 80% with early TIPSS with 90% power (alpha=0.05), and allowing for 20% attrition._x000D_ _x000D_ Study duration:_x000D_ 6 months set up, 4 years for recruitment including a 12 month pilot phase, 1 year follow up and 6 months analysis and reporting._x000D_ _x000D_ Expertise of team_x000D_ Leading clinical experts in the field who have conducted similar research in the past. The Clinical Trials Unit comprises the Director, statistician, and trial coordinators, with links to qualitative researchers and health economists.

Research activity codes: 6.4 SURGERY
Health categories: ORAL AND GASTROINTESTINAL