This study is a prospective, single-blind, randomized, multicenter study comparing the influence of shunting left or right branch of portal vein on post-TIPS hepatic encephalopathy in patients with HBV related cirrhosis. A total of 130 patients will be recruited over a period of 24 months across 5 centers in China. Centers will be chosen based on their potential to recruit a high number of patients, the expertise in TIPS treatment, and will receive special training with standard TIPS procedures and HE assessment. Eligible patients will be stratified 1:1 to constructing either left or right portal vein shunt with 8mm Viatorr stent (Fig. 1).
This study is conducted in accordance with the Declaration of Helsinki and current good clinical practice guidelines. This study is approved by the ethics committee of Zhongshan hospital of Fudan University (No. B2018-292R) and was registered at ClinicalTrials.gov (NCT03825848). All other participating centers have obtained the relevant ethics committee approval before patient enrolment.
Inclusion and exclusion criteria
The inclusion and exclusion criteria for the INSTIPHE trail are summarized in Table 1.
All relevant information regarding the clinical trial is included in informed consent forms in the Chinese language. Further, the principal investigators will provide a detailed explanation of this trial to the eligible patients. Informed consent must be signed by all patients or their relatives if the informed consent cannot be signed by the patients themselves. All patients’ personal data and medical information will be kept confidential. All patients will be permitted to with- draw from this trial at any time.
Eligible patients will be randomized 1:1 into shunting left (L Group) or right (R Group) branch of portal vein. The randomization will be stratified by center, Child-Pugh class (Child-Pugh Class A=5–6 points or Child-Pugh Class B=7–9 points) and the serial ammonia level (lower level £ 50 µmol/L or higher level >50 µmol/L) before TIPS. The list will be balanced by different sized blocks and randomly alternated. Patients will be blinded to randomization. The data coordination center of Fudan University will prepare the randomization.
All enrolled patients received TIPS within 72 hours of randomization. After transhepatic puncture of a secondary branch of intrahepatic portal vein under ultrasound guidance, a 5-F Pigtail catheter will be introduced into the splenic vein and superior mesenteric vein (SMV) to evaluate the index varices as well as the feeding vessels and draining veins. The main feeding vessel (e.g., left, short or posterior gastric vein) will be embolized with coils and N-butyl-2 cyanoacrylate (NBCA). Portal vein pressure and 5ml blood sample for serial ammonia concentration detection will be obtained at splenic vein, SMV, main portal vein and primary branch of intrahepatic portal vein separately. According to the randomization, the tip of Pigtail catheter will be placed at either left (L Group) or right (R Group) branch of portal vein (0.5 cm from the portal vein bifurcation) as a marker for conventional TIPS creation. Viatorr-covered stents (W. L. Gore & Associates, USA) with a diameter of 8 mm and a length of 6–10 cm will be employed in our study. Postoperative portal vein pressure will be measured at the main portal vein level. The transhepatic tract will be embolized with coils or NBCA after TIPS.
Low protein diet, intravenous L-ornithine-L-aspartate (20g qd) with branched-chain amino acids and oral lactulose (10ml tid) for 3 days will be routinely prescribed for the prevention of post-TIPS hepatic encephalopathy after TIPS.
The last enrolled patient will be followed up for 24 months after the start of treatment (D0). All other patients will be followed up until the final visit of the last enrolled patient. Patients will therefore be followed up for a maximum of 48 months and a minimum of 12 months following start of treatment. All patients will be assessed by the schedule summarized in Table 2.
Additional non-study assessments are permitted at the discretion of the treating investigator. Follow up will be discontinued if the patient receives liver transplantation, if the patient withdraws consent, or if a physician considers it necessary for the patient to discontinue the trial from a medical perspective
The primary endpoint of the INTIPHE trial is to compare the rate of post-TIPS hepatic encephalopathy between patients with left or right shunt at 12 months and 24 months.
The secondary endpoints include comparing the grade and duration of hepatic encephalopathy, the rate of shunt dysfunction, the rate of variceal rebleeding, the HE free survival, the cumulative patency rate of stent and the overall survival at 12 months and 24 months between two groups.
The Grade of HE was classified into covert HE (minimal HE and Grade I) and overt HE (Grade II to Grade IV) according to the severity of manifestation (Table 3). Stroop Test (EncephalApp developed by Jasmohan Bajaj) will be used to detect the minimal HE. An Off-Time and On-Time value >190 seconds will identify patient with covert HE. Grade I to Grade IV HE will be diagnosed by clinical examination. The starting time, duration, treatment and outcome of every episode will be recorded.
HE free survival (HEFS) is defined as the time from D0 to the first episode of HE.
Shunt dysfunction will be suspected in the condition of rebleeding and/or the maximum flow velocity within the shunt is less than 0.5 m/s or absent on color Doppler ultrasound (CDUS). Shunt will be further confirmed by portography if the shunt stenosis is greater than 50% and/or PSG is beyond 15 mmHg, and TIPS revision by balloon angioplasty and additional stent-placement will be planned.
Variceal rebleeding is defined as bleeding from gastroesophageal varices confirmed by upper gastrointestinal endoscopy.
Sample size calculation
There is currently no multi-center RCT study on comparing the rate of HE between HBV-related cirrhosis patients with shunting left/right portal vein branch. The sample size was determined on the basis of three single center study11-13: the rate of HE in the patients with left branch shunt was 19.4% (2 years after TIPS), 15.4% (2 years after TIPS) and 22.6% (1 year after TIPS), while the rate of HE in the patients with right branch shunt was and 43.8% (2 years after surgery), 37.5% (2 years after surgery), 28.6% (1 year after surgery). We presume that the rate of HE after 2 years of TIPS shunting left and right branch will be 16.9% and 33.1%, respectively. Considering a power of 80% with a bilateral alpha risk of 5% and a dropout rate of 10%, we aimed to enroll 130 patients.
All data will be analyzed on the intention-to-treat population. Continuous variables will be summarized as mean ± standard deviation or the median values (ranges) and will be compared using the independent sample t test or one-way analysis of variance. Categorical variables will be expressed as frequencies and compared using the Chi-Square or Fisher’s exact tests. The Kaplan and Meier method will be used to calculate cumulative risks. The comparison of survival and patency rates at 12 months and 24 months between the two treatment groups will be performed using the log rank test (Mantel-Haenszel version). Two-tailed p values <0.05 will be considered statistically significant. All statistical calculations will be performed using SPSS V.25.0 (Chicago, Illinois, USA).