A Randomized Controlled Study on the Effects of PPIs on Gastroesophageal Variceal Bleeding in Liver Cirrhosis (PPIs: Proton Pump Inhibitors)
Phase: PHASE4
Conditions: Liver Cirrhosis, Hypertension, Portal
Sponsor: Yanjing Gao

Official Title: A randomized controlled study on effects of proton pump inhibitor on 
gastroesophageal varices of cirrhosis 
Brief Title: PPIs and Gastroesophageal Varices in Liver Cirrhosis 
NCT Number: 03175731 
Unique Protocol ID: 2017037-QILU 
Document Date: 29/12/2020 
 
 

Study Protocol 
 
Patients’ selection 
Cirrhotic patients with GEVs will be considered for enrollment in this randomized 
controlled study from May 2017 and June 2019. The following inclusion criteria will 
be applied: (1) age ≥ 18 years; (2) diagnosed cirrhosis based on clinical, laboratory, and 
radiological parameters and/or liver biopsy; (3) diagnosed GEVs based on endoscopy. 
The exclusion criteria: (1) acute gastrointestinal bleeding requiring emergency surgery; 
(2) acid-related disease, such as peptic ulcer disease or gastroesophageal reflux diseases; 
(3) hepatocellular carcinoma or other malignant tumor; (4) history of surgery of the 
esophagus, stomach or liver; (5) Child–Pugh grade C disease that cannot be improved 
to grade A or B; (6) preparing to be pregnant, pregnant, or breast feeding; (7) PPI 
allergies; and 8) missing informed consent. 
 
Randomization and masking 
Randomization will be performed after GEVs confirmed by endoscopy. Eligible 
patients will be randomized into PPI and non-PPI groups in a 1:1 ratio using a computer-
generated list of random numbers. The numbers will be written on papers placed in 
sealed and opaque envelopes by an independent research assistant. After confirmation 
of GEVs by endoscopy and inclusion in this study, one envelope will be opened. The 
expert endoscopists will be blinded to the randomization and patient’s data. 
 
Procedures 
An initial endoscopy will be performed with endoscopic findings classified according 
to the grading system outlined in the guidelines released by Chinese Medical 

Association[8]. After an initial endoscopy, endoscopic therapy will be undertaken 
according to updated UK guidelines [6]. All participants enrolled in this study will be 
banded every 2 weeks; however, patients who suffered from rebleeding will receive 
rescue EVL/ETA as soon as possible. Endoscopic therapy will be performed by three 
expert endoscopists with more than 10 years of relevant experience. 
After endoscopic therapy, eligible patients will be randomly assigned to the PPI group 
(receive pantoprazole 40 mg/day intravenously/orally for 14 days) or the non-PPI group 
(do not receive PPI treatment). 
 
 
Statistical Analysis Plan 
To calculate the sample size, the overall variceal bleeding rate after endoscopic therapy 
will be chosen as the primary outcome. According to published data[9], and assuming a 

22% difference in the rate of variceal bleeding between the non-PPI group (27%) and 
the PPI group (5%), at least 46 patients will be required in each group to provide 90% 
confidence in the results, with the upper limit of the one-sided 95% confidence interval 
(α=0.05, β=0.10). Moreover, assuming a flow off rate of 10%, at least 100 patients will 
be required in this study. 
Quantitative variables will be compared using Student’s t-test or Mann–Whitney U-test, 
and the  2 test or Fisher’s exact test will be used to compare qualitative variables. The 
cumulative rate of bleeding will be calculated using the Kaplan–Meier method, and log-
rank tests will be performed for comparison of differences. P values <0.05 will be 
considered statistically significant.