Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000843752
Ethics application status
Approved
Date submitted
26/05/2022
Date registered
15/06/2022
Date last updated
22/07/2022
Date data sharing statement initially provided
15/06/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Feasible, safety and utility of Endoscopic ultrasound-guided PPG measurement (EUS-PPGM) in patients undergoing liver resection and major intra-abdominal surgeries.
Scientific title
Feasible, safety and utility of Endoscopic ultrasound-guided PPG measurement (EUS-PPGM) in patients undergoing liver resection and major intra-abdominal surgeries.
Secondary ID [1] 307151 0
none
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
portal hypertension 326350 0
cancer 326351 0
Cirrhosis 326352 0
Liver 326489 0
Condition category
Condition code
Oral and Gastrointestinal 323656 323656 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Cancer 323851 323851 0 0
Liver

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Portal hypertension is a consequence of cirrhosis of the liver. The portal pressure gradient (PPG) is defined as the difference in pressure between the portal vein and the inferior vena cava. Clinically significant portal hypertension occurs with a PPG of 10 mmHg or above. Portal hypertension is the main driver for the majority complications of cirrhosis. Clinically significant portal hypertension is associated with an increased risk of varices, overt clinical decompensation (manifest as ascites, hepatic encephalopathy and/or variceal haemorrhage), postsurgical decompensation, need for liver transplantation and death, among many other complications. Therefore, establishing the presence and severity of portal hypertension in a patient with cirrhosis is important for prognostication, risk stratification and to guide appropriate treatment.

The current gold standard for determining the portal pressure gradient indirectly via the transjugular approach and subsequent determination of the hepatic venous pressure gradient (HVPG).

EUS-PPGM technique
EUS-guided Portal Pressure Gradient Measurement (EUS-PPGM) approach is a newer technique, less invasive procedure to measure the portal pressure gradient directly. It is done under General anesthesia and the procedure will take around 30 mins. Each patient will undergo the procedure once prior to their surgery.

The apparatus for EUS-PPGM will comprise of a linear echoendoscope, a 25G FNA needle, and a compact manometer with non-compressible tubing (Cook Medical, Bloomington, IN). The tubing will be connected by a luer lock to the distal port of the manometer, while the heparinized saline will be connected to the proximal port. The end of the tubing is connected through a luer lock to the inlet of the 25G needle. This device has been approved by the respective governing body in New Zealand for clinical use.

First, a forward viewing endoscope will be inserted to document any endoscopic evidence of varices (including size and presence of red wale marks) as well as portal hypertensive gastropathy.

Prior to echoendoscope insertion, the manometer will be zeroed at the midaxillary line of the patient. The hepatic vein (HV) measurement will be conducted first. Doppler flow will be used to confirm the typical multiphasic waveform of hepatic venous flow. Using the 25G FNA needle, a transgastric transhepatic approach is used to puncture the HV. Approximately 1 mL of heparinized saline will be used to flush the needle which is visible on EUS to confirm good position within the vessel. After the initial rise in pressure reading as a result of flushing, the manometer reading will equilibrate at a steady pressure, which will then be measured three times. The mean of these three pressures is then considered the HV pressure. The FNA needle is then withdrawn from the vein into the liver parenchyma, and then back into the needle sheath. The needle tract within the liver parenchyma will be observed with Doppler flow on to ensure there is no flow within the needle tract.

Then the manometer will be disconnected. A separate manometer that is routinely to measure central venous pressure will be attached to the FNA needle and connect to the cardiac monitor with venous pressure waveform and numerical value display function. The manometer will be zeroed at the midaxillary line of the patient by pressing the central venous pressure ‘zero’ button on the cardiac monitor to calibrate the equipment. The CVL consists of a transducer board, fluid lines and a three-way tap. It will be necessary to administer IV fluid using a pressure bag to prime the line of the transducer with fluid to ensure it contains no air and is patent.

Three pressure measurements will be taken and the mean of these three pressures is then considered the HV pressure.
The FNA needle is then withdrawn from the vein into the liver parenchyma, and then back into the needle sheath. The needle tract within the liver parenchyma will be observed with Doppler flow on to ensure there is no flow within the needle tract.

The portal vein (PV) measurement will be conducted next. The umbilical portion of the left portal vein will be targeted, and Doppler flow will then be used to confirm the typical venous hum of portal venous flow. Using the 25G FNA needle, a transgastric transhepatic approach is used to puncture the PV. The procedure that follows is the same as what would have been performed for the HV. Three readings will be taken, the mean of which is considered the PV pressure. Then three measurements will be repeated with a different manometer which connects to the CVL and cardiac monitor display as the same as what would have been performed for the HV. The mean of these three readings will be recorded.

The patient is recovered in a similar manner to a routine diagnostic EUS with FNA, and postprocedural antibiotics are usually given for 3-5 days post procedure. The EUS-PPGM will be performed by experienced Endoscopist who had performed successfully in approximately 10 patients by very experienced Endoscopists in our Endoscopy unit in Waikato Hospital and this technique has been validated worldwide.

Given the safety of EUS and its availability in current clinical practice, the use of EUS-PPGM as a routine pre-operative assessment is much more feasible than the transjugular approach. It also provides an additional objective measurement in pre-surgical selection. This study, therefore, aims to assess the feasibility, safety and utility of Endoscopic ultrasound-guided PPG measurement (EUS-PPGM) in patients undergoing liver resection and major intra-abdominal surgeries.

This will be an open labelled, non-randomised, pilot prospective study to evaluate the role of EUS approach in assessing the portal pressure gradient in comparison to the transjugular approach in patients with cancer in the liver who are recommended to undergo abdominal surgery, liver resection or liver transplantation.

The patients who are adults Maori and non-Maori will be recruited from the Upper
Gastrointestinal multidisciplinary team meetings conducted at the Waikato Hospital, Hamilton.

The patients will then be reviewed in the General Surgical outpatient clinic to discuss the potential surgical treatment options.

In addition, the study will be introduced to the patients and their whanau, patient information sheet and consent form of the study will be given.

Investigators will also contact the potential participants via phone or face-face clinic to check
if they have any questions or concerns regarding the study. On the days of the endoscopic
and radiologic procedures, the endoscopist and radiologist will also meet the patients to
explain the procedure again and answer any questions or concerns.
Intervention code [1] 323606 0
Diagnosis / Prognosis
Comparator / control treatment
The comparator is the current gold standard - transjugular approach in assessing the portal pressure gradient in patients with cancer in the liver who are recommended to undergo abdominal surgery, liver resection or liver transplantation.

This will be performed by an experienced interventional radiologist who has received specific training in performing transjugular HVPG measurements at Waikato Hospital. We will use the standard technique, as outlined by Abraldes et al. Under local anaesthesia and light sedation, a venous catheter introducer sheath will be placed in the right jugular vein, antecubital vein or femoral vein under ultrasound guidance using the Seldinger technique. Under fluoroscopy, a balloon-tipped catheter will be advanced into a main HV. The FHVP will then be measured with the tip of the catheter in the HV at 2 – 4 cm from its opening into the inferior vena cava. The balloon of the catheter will be inflated to occlude the HV, and occlusion will be confirmed by injection of 5 mL of contrast dye. The measurement of the WHVP will then follow. Each of the WHVP and FHVP measurements will be taken in triplicate, and the mean FHVP will be subtracted from the WHVP to calculate the HVPG.

All the participants will undergo the gold standard measurement - the transjugular approach as well as the new technique EUS approach so that we can compare the feasibility, utility and safety of the EUS technique.
Control group
Active

Outcomes
Primary outcome [1] 331400 0
Our primary outcome will be post-operative liver dysfunction, which is defined as:
(i) serum bilirubin level > 5 mg/dL (> 85.5µmol/L) on or after postoperative day 5;
- Blood test will be taken from the participants as part of the routine blood test
Timepoint [1] 331400 0
on or after postoperative day 5 after operation
Primary outcome [2] 331594 0
(ii) coagulopathy (INR > 2.0 associated with haemorrhagic complications requiring transfusion);
- Blood test will be taken from the participants as part of the routine blood test
Timepoint [2] 331594 0
on or after postoperative day 5 after operation
Primary outcome [3] 331595 0
(iii) hepatic encephalopathy
- clinical assessment and examination will be carried out to assess for hepatic encephalopathy
Timepoint [3] 331595 0
on or after postoperative day 5 after operation
Secondary outcome [1] 409730 0
Our 4th primary outcome will be post-operative liver dysfunction, which is defined as: (iv) abdominal ascites (drainage volumes more than 500 ml/day after day 3).
- clinical assessment and examination will be carried out to assess for ascites
Timepoint [1] 409730 0
day 3 post operation
Secondary outcome [2] 410376 0
Our secondary outcomes will be as follows:
· Complications related to Endoscopic ultrasound portal pressure gradient measurement (EUS PPGM) and transjugular hepatic venous pressure gradient (TJ-HVPG) approaches
- The method of assessment through review of medical records, blood test, admissions or clinical review related to adverse events from the either approaches.
Timepoint [2] 410376 0
up to 90 days post operation
Secondary outcome [3] 410377 0
Complications related to surgery and recovery
- The method of assessment through review of medical records, blood test, admissions or clinical review related to adverse events from the surgery and report from surgeons
Timepoint [3] 410377 0
up to 90 days post operation
Secondary outcome [4] 410378 0
Transfusion need
- The method of assessment through review of medical records and blood test
Timepoint [4] 410378 0
up to 90 days post operation
Secondary outcome [5] 410380 0
Cost differences between EUS PPGM and TJ-HVPG approaches
- by review of hospital financial records between the two approaches,
Timepoint [5] 410380 0
up to 90 days post operation
Secondary outcome [6] 410381 0
Length of hospital stay
- by review of medical records
Timepoint [6] 410381 0
up to 90 days post operation
Secondary outcome [7] 410382 0
90-day mortality
Timepoint [7] 410382 0
90 days post operation
Secondary outcome [8] 410383 0
Outcome and complications between Maori and non Maori patients
- both will be considered together as a composite outcome
- by review of medical records, clinical examination, and report by surgeon
Timepoint [8] 410383 0
up to 90 days post operation

Eligibility
Key inclusion criteria
Inclusion criteria:
· Patients with cancer in the liver (with or without cirrhosis) who are recommended for liver resection or liver transplant
· Patients with cirrhosis who are recommended to undergo abdominal surgery
Minimum age
15 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria
· International Normalised Ratio (INR) > 1.6 (as part of the standard of care)
· Significant ascites
· Child-Pugh C severity of cirrhosis
· Presence of large gastric varices or periportal collateral vessels that prevent EUS approach to the hepatic and/or portal vasculature

Study design
Purpose of the study
Diagnosis
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Sample size
Based on the study by Boleslawski et al., a sample size up to 40 subjects was sufficient to demonstrate that a raised HVPG (>10mmHg) was associated with a significant rate of post-operative liver dysfunction and higher 90-day mortality. Given this is a pilot study, we proposed of adopting the similar sample size (n=40) to examine the role of EUS PPGM assessment.

Analysis
Continuous variables, reported as medians and range, will be compared using the Mann-Whitney test. Categorical data, which will be presented as frequencies (%) will be compared using the Chi-square test or Fischer’s exact test, as appropriate. The accuracy of the EUS-PPG in predicting Post hepatectomy liver failure (PHLF) will be assessed by measuring the area under the receiver operating characteristics (AUROC) curve, and differences between AUROCs will be compared using the Hanley-McNeil method. Positive and negative predictive values for the PPG cut-off point of = 10 mmHg will be calculated and reported. Differences in survival between patients with and without EUS-PPG measurement = 10 mmHg will be assessed by the Kaplan-Meier method, with differences in survival estimates tested by the log rank test. A significance level of 0.05 will be used in all analyses.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
29/07/2022
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
40
Accrual to date
Final
Recruitment outside Australia
Country [1] 24778 0
New Zealand
State/province [1] 24778 0

Funding & Sponsors
Funding source category [1] 311454 0
Government body
Name [1] 311454 0
Waikato District Health Board - Waikato Hospital
Country [1] 311454 0
New Zealand
Primary sponsor type
Government body
Name
Waikato District Health Board - Waikato Hospital
Address
Waikato hospital
183 Pembroke Street, Waikato Hospital,
Hamilton 3204
Country
New Zealand
Secondary sponsor category [1] 312852 0
None
Name [1] 312852 0
Address [1] 312852 0
Country [1] 312852 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310926 0
Southern Health and Disability Ethics Committee
Ethics committee address [1] 310926 0
Ethics committee country [1] 310926 0
New Zealand
Date submitted for ethics approval [1] 310926 0
22/04/2022
Approval date [1] 310926 0
15/06/2022
Ethics approval number [1] 310926 0
2022 FULL 11858

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 119374 0
Dr Frank Weilert
Address 119374 0
183 Pembroke Street, Waikato Hospital
Hamilton 3204
Country 119374 0
New Zealand
Phone 119374 0
+6421417473
Fax 119374 0
Email 119374 0
[email protected]
Contact person for public queries
Name 119375 0
Frank Weilert
Address 119375 0
183 Pembroke Street, Waikato Hospital
Hamilton 3204
Country 119375 0
New Zealand
Phone 119375 0
+6421417473
Fax 119375 0
Email 119375 0
[email protected]
Contact person for scientific queries
Name 119376 0
Frank Weilert
Address 119376 0
183 Pembroke Street, Waikato Hospital
Hamilton 3204
Country 119376 0
New Zealand
Phone 119376 0
+6421417473
Fax 119376 0
Email 119376 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
No participant data will not be publicly available due to privacy reason.
The data will be collected by the study investigators, de-identified, coded, and then stored in the secure area of the Department of Gastroenterology. Only the investigators and staff of the Department of Gastroenterology research staff will have access to the records. Results from this study will be published in a peer reviewed journal. All records will be kept for 25 years in the Discipline of Medicine and the study will maintain the anonymity of the subjects.


What supporting documents are/will be available?




Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.