Clinical trial NCT04786743: Timing of Endoscopic Intervention for Acute Variceal Hemorrhage: an RCT
Official title: Timing of Endoscopic Intervention in Patients With Cirrhosis With Acute Variceal Upper Gastrointestinal Hemorrhage (TEACH Trial): a Randomized Clinical Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Acute Upper Gastrointestinal Hemorrhage
Cirrhosis
Varice Bleed
Gastroesophageal Varices
Keywords: Endoscopic intervention; Acute variceal hemorrhage; RCT
Lead sponsor: Jinling Hospital, China
Sponsor class: OTHER
Collaborators: name: The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
name: The first affiliated Hospital of Nanjing Medical University, Jiangsu Province
name: The Affiliated Wuxi People's Hospital of Nanjing Medical University
name: Taixing People's Hospital
First posted: 2021-03-08
Enrollment: 400
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Eligible patients are randomly assigned in a 1:1 ratio to receive endoscopic intervention either within 6h or 6-24h. Randomization is conducted by permuted block randomization stratified by age, systolic blood pressure (SBP), and pulse rate. The block size is pre-specified, but physicians and investigators are not notified of this during the study. Allocation concealment is implemented by the mobile client randomization tool "Randomization Allocation Tool (RAT)".
Primary purpose: TREATMENT

Brief summary: Acute variceal upper gastrointestinal hemorrhage remains a hot potato in cirrhotic patients. The purpose of this study is to figure out whether urgent endoscopy (within 6h after gastroenterological consultation) is superior to non-urgent endoscopy (between 6h and 24h after gastroenterological consultation) in reducing rebleeding for these patients. This is a multi-centered, prospective, randomized, and controlled trial. 400 patients with suspected variceal bleeding will be randomized in a 1:1 ratio to receive endoscopic intervention either within 6h or 6-24h. Randomization is conducted by permuted block randomization stratified by age, systolic blood pressure (SBP), and pulse rate. The primary efficacy endpoint is rebleeding within 42 days after control of acute variceal hemorrhage. This trial will provide valuable insights into the efficacy between the urgent endoscopy group and the non-urgent endoscopy group.

Detailed description: Study design

The study protocol observes the Standard Protocol Items rules: Recommendations for Interventional Trials (SPIRIT) 2013. The leader of the sponsoring organization strictly implements oversight of the protocol. We intend to compare the effectiveness of improving rebleeding rates of cirrhotic patients with acute variceal hemorrhage (AVH) between the urgent endoscopy and non-urgent endoscopy groups. The study started on April 20, 2021, and was initially designed as a single-center study. However, due to the impact of the COVID-19, case enrollment was greatly challenged, and our study was put on hold for about 8 months. To ensure the smooth progress of this study, we submitted the application for adding the research centers to the Ethics Committee of affiliated Jinling Hospital, Medical School of Nanjing University (the organizing center) in April 2023, and in May, we obtained the consent of the Ethics Committee of Jinling hospital and carried out the study in five medical centers. Until September 2024, we have collected more than 300 patients. In this study, we plan to conduct a multi-centered, prospective, parallel-group randomized clinical trial. Informed consent forms from every patient will be signed before enrollment, and approval from the Ethical Committees of Jinling Hospital has been obtained (the authorized ethics numbers were DZQH-KYLL-21-0101 and 2023DZKY-031-03). Furthermore, the study protocol was also approved by the ethics committees of each medical center.

Data processing

Two investigators in every department are responsible for the data collection and storage. One investigator will inspect the data collected by the other investigator. After completing the inspection, the data, which are open to the analysts, will be kept in secret and input into the offline database constructed by the investigators. As soon as they complete all the data storage, the two investigators will conduct a double inspection. The collected data will be used for data analysis. The investigators will strictly follow the study protocol to inspect, collect, record and preserve the data in a timely manner to minimize the occurrence of missing data. If missing data occur in a small percentage of patients, we will handle it with multiple imputation. We will perform source data verification by comparing them with authentic medical records to assess the accuracy, completeness, and representativeness of registry data.

Patients enrollment

An estimated 400 patients will be consecutively included in the study between April 2021 and June 2025. Patients or their statutory agents must provide written, informed consent before participating in any of the study procedures. The model for end-stage liver disease (MELD) score, Child-Pugh score and original GBS, instead of the modified version, will be used to evaluate the condition of each patient.

Sample size

According to a study by Ardevol A et al, among 646 cirrhotic patients with AVH who underwent endoscopy within 6 h after admission, the 45-day rebleeding rate was 26%, which was similar to that in another study by Chen PH et al, who reported that the overall 6-week rebleeding rate was 25.7%. Then, we assumed a clinically significant difference of 14% to implement this exploratory trial and provide support for further confirmatory trials. Next, we calculated that having at least 189 patients in each group would reveal differences (26% vs. 40%), with a statistical power of 80% and a two-sided α level of 5%. Considering withdrawal and loss to follow-up, the sample size was increased to 200 patients per group.

Randomization and time set

Eligible patients will be randomly assigned in a 1:1 ratio to receive endoscopic intervention either within 6 h or between 6 and 24 h after gastroenterological consultation. Randomization will be conducted by permuted block randomization stratified by age (≥60 years or \<60 years), systolic blood pressure (SBP) (≥90 mmHg or \<90 mmHg), and pulse rate (≥100 beats/min or \<100 beats/min). The purpose of using stratified randomization is to reduce the imbalance of covariates because they are strongly correlated with the outcome indicators between groups, and to further control bias. The block size is prespecified, but physicians and investigators will not be notified of this fact during the study. The randomization sequence generation and allocation concealment will be implemented by the mobile client randomization tool "Randomization Allocation Tool (RAT)". There are two primary sources of patients. Most of these patients are from the emergency department, and the others are cirrhotic patients who developed AVH during hospitalization. For patients from the emergency department, the interval between admission and receiving gastroenterological consultation will be controlled within 10 minutes by applying the emergency green channel in our center. However, for patients who develop AVH during hospitalization, the time will be recorded according to when they are evaluated by the emergency endoscopy team (i.e., gastroenterological consultation). To facilitate data recording, the time will be uniformly calculated for all patients according to when the gastroenterological consultation is received. The patients will be randomly allocated to undergo urgent endoscopy within 6 h or non-urgent endoscopy between 6 h and 24 h after gastroenterological consultation. The following time data will be recorded: (I) time from presenting with symptoms of AVH to admission (patients from the emergency department); (II) time from admission to gastroenterological consultation (patients from the emergency department); (III) time from presentation to gastroenterological consultation (all of the patients); and (IV) time from gastroenterological consultation to endoscopic intervention (all of the patients).

Control of AVH, persistent bleeding, and rebleeding

AVH under endoscopy mainly refers to blood gushing or seeping from esophageal or gastric varices; however, if there is no blood gush or seepage detected, thrombus stigmata attached to varices together with massive hematocele of the stomach will also be regarded as one kind of AVH under endoscopy. Control of AVH refers to a lack of persistent bleeding signs within 24 h after the initial endoscopic intervention; otherwise, the patients will be regarded as having persistent bleeding, which is defined as the occurrence of at least one of the following items: (I) vomiting of fresh blood or suction of more than 100 ml of fresh blood from the nasogastric tube; (II) occurrence of hemorrhagic shock; and (III) decrease in hemoglobin level of 30 g/L in the absence of a blood transfusion. Rebleeding refers to recurrent bleeding after the control of AVH, which is defined as the occurrence of at least one of the following items: (I) hematemesis, melena or hematochezia; (II) decrease in SBP of more than 20 mmHg from the original level or an increase in heart rate of 20 beats/min; and (III) decrease in hemoglobin level of 30 g/L in the absence of a blood transfusion. Patients with persistent bleeding or rebleeding will immediately undergo a secondary endoscopic intervention or be transferred for other salvage treatment (surgery, percutaneous transhepatic variceal embolization \[PTVE\] or transjugular intrahepatic portosystemic stent shunt \[TIPSS\]) according to the their condition and wishes. Although the vast majority of acute hemorrhage and rebleeding is caused by esophagogastric varices in this trial, acute hemorrhage and rebleeding caused by non-variceal factors will also be recorded and included in the statistical analysis.

Treatment

(I) Before endoscopic intervention: all patients will receive uninterrupted intravenous administration of high-dose PPIs (8 mg/h) and somatostatin (250 μg/h) and antibiotic prophylaxis; (II) Initial endoscopic intervention: patients who have nonvariceal bleeding under endoscopy will not be excluded from this trial; as patients are screened strictly according to the inclusion and exclusion criteria, there will theoretically not be many of these patients. Moreover, professional academic statisticians will conduct intent-to-treat analysis and per-protocol analysis, which are described in detail in the following statistical analysis. For patients meeting the criteria for AVH, numerous methods could be applied, including histoacryl injection, sclerotherapy, variceal ligation, a covered stent or combinations of these. The patient's position will be chosen to expose the best field of view under endoscopy, and an external cannula for endoscopy could be used to prevent asphyxiation. Furthermore, initial endoscopic intervention will be aimed solely at the bleeding site. After endoscopic intervention, we will transfer the patient to the general ward or intensive care unit (ICU) according to the patient's condition.

(III) After the initial endoscopic intervention: all the patients will be treated with continuous high-dose PPIs (8 mg/h) and intravenous infusion of somatostatin (250 μg/h) for 72 h, together with the preventive administration of antibiotics for no more than 120 h; during the follow-up, oral propranolol and ultrasound-guided histoacryl injection could be used as secondary preventive measures according to the patient's condition.

(IV) The emergency endoscopy team consists of three experienced endoscopists, each with more than ten years of experience in endoscopy and over 500 cases of variceal hemostasis experience under endoscopy. Furthermore, several seasoned endoscopic nurses who are proficient in applying endoscopic treatment instruments and cooperating with endoscopists will also be included.

Follow-up time

After randomization, follow-up work will begin. All the patients included will be followed up for no less than 42 days after controlling for AVH. When the patients' conditions are stable, further treatment of varices will be determined according to their wishes and statutory agents. Patients with good compliance will be administered standard endoscopic secondary prophylaxis after 5 days of AVH control, and the follow-up time should be once a week. Patients who decline to accept further endoscopic intervention will undergo only weekly follow-up. Follow-up could be in the form of a telephone or outpatient review. Follow-up will be regarded as complete at the time of death or in accordance with the follow-up deadline.

Statistical analysis

Primary analyses for the primary efficacy endpoint between the urgent endoscopy and non-urgent endoscopy groups will be performed in the intention-to-treat population, which will include all patients who are randomized to a study therapy group, regardless of whether they receive the endoscopic intervention. Multiple imputations with the Markov chain Monte Carlo method will be applied to impute the missing endpoints. Secondary analyses will be based on the per-protocol population, which will include all patients who receive the intended endoscopic intervention without a major protocol violation or loss to follow-up.

Descriptive statistics will be used to compare patients randomized to the urgent endoscopy and non-urgent endoscopy groups with respect to baseline variables. Continuous variables will be expressed as the means and standard deviations (normally distributed) or medians and interquartile ranges (non-normally distributed). Assessments of normality for continuous variables will be performed using the Shapiro-Wilk test. Categorical variables will be calculated as frequencies and percentages.

For the primary analyses, the rebleeding rates within 42 days will be compared between the two groups using the chi-square tests and the Cochran-Mantel-Haenszel tests, and their differences and corresponding 95% confidence intervals (CIs) will be calculated. Additionally, the rebleeding rates will be estimated using the Kaplan-Meier method. The log-rank test will be used to compare the difference in rebleeding rates between the two groups. A Cox proportional hazards regression model will be used to estimate the hazard ratio (HR) and its 95% CI. The proportional hazards assumption will be assessed using the Schoenfeld residual test. Furthermore, the Cox regression model will be performed to assess the consistency of the endoscopy regarding the primary efficacy endpoint, taking the randomization stratification factor into consideration. Except for age, SBP, and pulse rate, the subgroup analysis also included sex, the severity of liver disease, etc. For these subgroup analyses, HRs and 95% CIs for the primary efficacy endpoint will be calculated for each subgroup, and subgroup differences will be assessed based on the test for the interaction of the treatment group by subgroup in the model. Additionally, the Cox regression model will also be performed as a sensitivity analysis to assess the effect of endoscopy on the primary efficacy endpoint while accounting for a priori clinically important baseline characteristics (e.g., age, sex, Child-Pugh score, MELD score, etc.). Two-tailed p values will be used, and a p value of \<0.05 will be indicative of statistical significance.

The secondary efficacy endpoints will be assessed in the per-protocol population and compared between the two groups with chi-square test for differences in proportions and with Student's t test and Wilcoxon's rank-sum test for normally distributed and non-normally distributed data, respectively. The results for secondary efficacy endpoints will also be presented with 95% CIs. As they will not be adjusted for multiplicity, findings for the analysis of secondary efficacy endpoints should be interpreted as exploratory. All analyses will be performed using SAS software (version 9.4; SAS Institute).

Eligibility criteria: Inclusion Criteria:

(I) patients who have pathological or clinical and imaging evidence indicating a diagnosis of cirrhosis; (II) patients with clinical symptoms associated with AVH (hematemesis, melena or hematochezia) before admission or during hospitalization; (III) patients who are hemodynamically stable before or after initial fluid resuscitation.

Exclusion Criteria:

(I) pregnancy; (II) lactation; (III) less than 18 years; (IV) patients with a history of taking anticoagulant or antiplatelet drugs within 2 weeks prior to admission.

Primary outcomes:
measure: Rebleeding
timeFrame: 42 days
Secondary outcomes:
measure: All-cause mortality
timeFrame: 42 days
measure: Persistent bleeding
timeFrame: 1 day
measure: length of hospitalization
timeFrame: 42 days
measure: Transfers to the ICU
timeFrame: 42 days
measure: Secondary endoscopic intervention
timeFrame: 42 days
measure: Blood transfusion therapy
timeFrame: 42 days
measure: Concurrent infection
timeFrame: 42 days
measure: 5-day treatment failure
timeFrame: 5 days
Other outcomes:
Locations:
city: Nanjing
country: China
facility: Affiliated Jinling Hospital, Medical School of Nanjing University
state: Jiangsu
city: Nanjing
country: China
facility: Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School
state: Jiangsu
city: Nanjing
country: China
facility: First Affiliated Hospital of Nanjing Medical University
state: Jiangsu
city: Taixing
country: China
facility: Taixing People's Hospital
state: Jiangsu
city: Wuxi
country: China
facility: The Affiliated Wuxi People's Hospital of Nanjing Medical University
state: Jiangsu
Study officials:
affiliation: Jinling Hospital, China
name: Fangyu Wang, M.D.
role: PRINCIPAL_INVESTIGATOR
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