Bloody or Well Done. How Would You Like Your Liver Biopsy, Sir? (LIMPID)

May 6, 2024 updated by: Mihai Ciocirlan, Carol Davila University of Medicine and Pharmacy

Bloody or Well Done. How Would You Like Your Liver Biopsy, Sir? Post Liver bIopsy abdoMinal PaIn as Predictive Factor for Liver bleeDing (LIMPID)

This is a randomized comparative trial between percutaneous liver biopsy and EUS FNB guided liver biopsy in patients with parenchymal liver disease.

Studies so far have been shown that EUS FNB guided liver biopsy is non inferior to percutaneous liver biopsy in terms of efficacy, provided several conditions are met (type of needle, wet suction, actuations).

În terms of safety, it may be that EUS FNB have an advantage, as needle diameter is slightly smaller, needle is inserted under better visualisation especially in patients with large subcutaneous fat tissue and the possibility of examining the needle tract and plugging it with needle content if needed ("the blood patch technique").

However, although severe, the incidence of liver bleeding is low, so a comparative trial with the hypothesis that EUS FNB has fewer liver bleedings than percutaneous techniques would have a very large sample size.

A recent study found out that abdominal pain at 2 hours after procedure is predictive for liver bleeding.

So we have design a randomized prospective trial assuming that EUS FNB guided liver biopsy has significantly less abdominal pain at 2 hours after procedure when compared to percutaneous route, using abdominal pain at 2 hours as a surrogate marker for risk of liver bleeding.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Why liver biopsy? Parenchymal liver diseases need sometimes diagnostic or staging assessment liver biopsy (eg. autoimmune hepatitis, primary biliary cholangitis, metabolic dysfunction associated fatty liver disease - MAFLD). Also, some focal liver lesions may need a diagnostic liver biopsy (eg. primitive liver tumors, liver metastases).

This can be performed percutaneously, trans-jugular and more recently trans-gastric or trans-duodenal under endoscopic ultrasound (EUS) guidance. The trans-jugular route was proposed for patients with coagulation disorders, as there is virtually no risk of bleeding, as the procedure is done within the supra-hepatic veins.

Currently, evidence exist that optimal results for EUS guided fine needle biopsy (FNB) are obtained by using a 19 Gauge Franseen FNB needle, by the heparin primed "wet suction" technique, with one or two passes (in both liver lobes), with at least 3 needle actuations [1,2,3,4]. Ensuring these conditions, the outcomes are non-inferior to percutaneous liver biopsy (length of the specimen, number of portal tracts, diagnostic accuracy).

So why choose EUS guided liver FNB? Two percutaneous liver biopsy adverse reactions are probably responsible for one's apprehension towards it - post procedure abdominal pain and the risk of liver bleeding. A recent meta-analysis [5] has found an incidence of mild abdominal pain at 12.9% and moderate-severe abdominal pain at 0.34%. The percentages for liver bleeding were 0.48% for major bleeding, 0.11% for major hematoma, 0.06% for hemoperitoneum and 0.01% for haemobilia (0.66% in total).

Bisonnette et al [6] have tried to find predictive factors for liver bleeding after percutaneous or trans-jugular liver biopsy. The only predictive factor was pain at 2h liver biopsy. This was more frequent following percutaneous than trans-jugular liver biopsy (33% vs. 15%; p < .001). Out of all patients with pain 2 h after liver biopsy, 15% had a liver biopsy-related bleeding, while out of those without pain 2 h after liver biopsy, 4% had a liver biopsy-related bleeding (p = .002). Pain 2 h after liver biopsy had a 55% (95% CI 0.35-0.73) sensitivity, 75% (95% CI 0.70-0.80) specificity, and 96% (95% CI 0.93-0.97) negative predictive value for liver biopsy -related bleeding.

EUS guided liver FNB seems to be safer than percutaneous liver biopsy. Eleven studies so far on 632 patients who had EUS FNB with 19G Franseen needle report on post procedure liver bleeding and abdominal pain [7-17]. Abdominal pain was present in 7.7%. of cases (28 of 362 reported patients), while liver bleeding was present in 0.16% (1 of 593, as "bile leak").

If we we're to design a study to prove that EUS guided liver FNB decreases bleeding rate from 0.66% for percutaneous route to 0.16%, with a type I error probability of 5% and a power of 80%, we would need to include 5126 patients, that is 2563 for each arm in a 1:1 allocation [7]. This is a near impossible study.

However, as Bisonnette et al [6] have proven, pain at 2h after liver biopsy is predictive for liver bleeding. So, we only need to prove that EUS guided liver FNB significantly decreases abdominal pain at 2h after procedure as compared to percutaneous route.

So, to prove that EUS guided liver FNB decreases abdominal pain rate at 2h after biopsy from 33% for percutaneous method to 7.7%, with a type I error probability of 5% and a power of 80%, we would need to include 78 patients, that is 39 for each arm in a 1:1 allocation [7].

Question of the research project We aim to answer the question whether EUS guided liver FNB has a significantly lower rate of abdominal pain at 2h after procedure than percutaneous liver biopsy.

Hypothesis The EUS guided liver FNB has a significantly lower rate of abdominal pain at 2h after procedure than percutaneous liver biopsy, which probably translates in a significantly lower liver bleeding rate.

Patients will be randomly allocated in one of the 2 study groups, following a randomization list (www.random.org), as it follows:

  • Group one - percutaneous (P)
  • Group two - EUS FNB (E)

Group one (P) - Percutaneous procedure will be performed under standard conditions, under transabdominal ultrasound guidance. After choosing the optimum needle trajectory, the skin site will be marked, standard skin sterilization with iodine and surgical draping of the site will be performed. Local anesthesia of the site with gradual lidocaine solution infiltration of the skin and underlying planes will be performed. Under ultrasound guidance, with collaboration of the patient for the respiratory movements, one or two passages with a 16G needle will be performed (BARD Max Core 16G, Becton Dickinson, USA). Specimens will be collected in formalin and send to pathology for processing.

Group two (E) - EUS guided liver FNB will be performed under deep sedation with propofol under anesthesiology monitoring. A 19G gauge Franseen needle (Acquire 19G, Boston Scientific, USA) will be used with the "wet suction" technique. Before inserting into the operating channel, the stylet will be removed, and the needle will be primed with heparin (500UI/5ml). After liver puncture, the 20ml aspiration syringe will be attached. Three needle actuations will be performed, one or two passes in the left liver lobe. At the end of the 3rd actuation, the syringe aspiration will be stopped, the needle will be left in place in the liver parenchyma for 2 to 3 minutes. The liver needle path will be examined with Doppler ultrasound to look for possible bleeding. If present, about 25% of the needle content will be pushed in the liver path, as previously described - the "blood patch" technique [19].

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
78

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Locations

  • Romania
      • Bucharest, Romania, 0112013
        • Recruiting
        • "Prof. Dr. Agrippa Ionescu" Clinical and Emerency Hospital
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Diffuse parenchymal liver disease with indication for liver biopsy for diagnostic and/or staging purposes,
  • Eligibility for deep sedation with propofol
  • Age above 18 years old
  • Informed consent

Exclusion Criteria:

  • Coagulation disorders which cannot be corrected
  • Anticoagulant and/or antiagregant medication which cannot be stopped temporarily.
  • Contraindications for liver biopsy, to local lidocaine anesthesia and to deep propofol sedation
  • Absence of written informed consent

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Diagnostic
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Active Comparator: Group one - percutaneous (P)
Percutaneous procedure will be performed under standard conditions, under transabdominal ultrasound guidance. After choosing the optimum needle trajectory, the skin site will be marked, standard skin sterilization with iodine and surgical draping of the site will be performed. Local anesthesia of the site with gradual lidocaine solution infiltration of the skin and underlying planes will be performed. Under ultrasound guidance, with collaboration of the patient for the respiratory movements, one or two passages with a 16G needle will be performed (BARD Max Core 16G, Becton Dickinson, USA). Specimens will be collected in formalin and send to pathology for processing.
Procedure: Group one - percutaneous (P)
Percutaneous procedure will be performed under standard conditions, under transabdominal ultrasound guidance. After choosing the optimum needle trajectory, the skin site will be marked, standard skin sterilization with iodine and surgical draping of the site will be performed. Local anesthesia of the site with gradual lidocaine solution infiltration of the skin and underlying planes will be performed. Under ultrasound guidance, with collaboration of the patient for the respiratory movements, one or two passages with a 16G needle will be performed (BARD Max Core 16G, Becton Dickinson, USA). Specimens will be collected in formalin and send to pathology for processing.
Active Comparator: Group two - EUS FNB (E)
EUS guided liver FNB will be performed under deep sedation with propofol under anesthesiology monitoring. A 19G gauge Franseen needle (Acquire 19G, Boston Scientific, USA) will be used with the "wet suction" technique. Before inserting into the operating channel, the stylet will be removed, and the needle will be primed with heparin (500UI/5ml). After liver puncture, the 20ml aspiration syringe will be attached. Three needle actuations will be performed, one or two passes in the left liver lobe. At the end of the 3rd actuation, the syringe aspiration will be stopped, the needle will be left in place in the liver parenchyma for 2 to 3 minutes. The liver needle path will be examined with Doppler ultrasound to look for possible bleeding. If present, about 25% of the needle content will be pushed in the liver path, as previously described - the "blood patch" technique
Procedure: Group two - EUS FNB (E)
EUS guided liver FNB will be performed under deep sedation with propofol under anesthesiology monitoring. A 19G gauge Franseen needle (Acquire 19G, Boston Scientific, USA) will be used with the "wet suction" technique. Before inserting into the operating channel, the stylet will be removed, and the needle will be primed with heparin (500UI/5ml). After liver puncture, the 20ml aspiration syringe will be attached. Three needle actuations will be performed, one or two passes in the left liver lobe. At the end of the 3rd actuation, the syringe aspiration will be stopped, the needle will be left in place in the liver parenchyma for 2 to 3 minutes. The liver needle path will be examined with Doppler ultrasound to look for possible bleeding. If present, about 25% of the needle content will be pushed in the liver path, as previously described - the "blood patch" technique.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Post procedure pain at 2 hours after procedure
Time Frame: 2 hours
Post procedure pain at 2 hours measured by Visual Analogue Scale (0 - 10)
2 hours

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Post procedure pain at 24 hours after procedure
Time Frame: 24 hours
Post procedure pain at 24 hours measured by Visual Analogue Scale (0 - 10)
24 hours
Proportion of post procedure liver bleeding
Time Frame: 7 days
Proportion of post procedure liver bleeding = number of patients with (perihepatic fluid, hemoperitoneum, liver hematoma, hemorrhagic shock) divided by the total number of patients enrolled in one arm
7 days
Longest intact specimen
Time Frame: 2 hours
Length (mm) of the longest intact specimen removed by biopsy for one patient
2 hours
Aggregate specimen length
Time Frame: 2 hours
Sum of the length of all the specimens (mm) removed by biopsy for one patient
2 hours
Total number of specimens
Time Frame: 2 hours
Sum of the number of specimens removed by biopsy for one patient
2 hours
Proportion of specimens > 20mm in aggregate length
Time Frame: 2 hours
Proportion of specimens > 20mm in aggregate length = number of patients with aggregate length of specimens (secondary outcome 5) > 20mm divided by the total number of patients enrolled in one arm
2 hours
Total specimen complete portal tracts (CPT)
Time Frame: 28 days
Sum of CPT for all specimens removed by biopsy for one patient
28 days
Proportion of specimens with > 11 CPT
Time Frame: 28 days
Proportion of specimens with > 11 CPT = number of patients with specimens > 11 CPT divided by the total number of patients in each arm
28 days
Proportion of specimen with conclusive pathological diagnosis
Time Frame: 28 days
Proportion of specimen with conclusive pathological diagnosis = number of patients with conclusive pathological diagnosis divided by the total number of patients in each arm
28 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Carol Davila University of Medicine and Pharmacy

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

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Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
May 6, 2024

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 1, 2024

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 1, 2024

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
January 9, 2024

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 21, 2024

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
January 30, 2024

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
May 7, 2024

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 6, 2024

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
May 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • LIMPID

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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