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Preventing Liver Cancer Mortality Through Imaging With Ultrasound vs. MRI (PREMIUM)

Primary Purpose

Carcinoma, Hepatocellular, Cirrhosis

Status
Not yet recruiting
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Abbreviated Magnetic Resonance Imaging with serum AFP
Abdominal Ultrasound Screening with serum AFP
Sponsored by
VA Office of Research and Development
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Carcinoma, Hepatocellular focused on measuring hepatic, oncology, liver, chronic diseases; health services and systems, prospective, randomized, clinical trial, magnetic resonance imaging; ultrasonography, cirrhosis; liver cancer

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Cirrhosis due to any underlying etiology diagnosed by one or more of the following:

    • Histology of liver biopsy
    • Radiologic criteria (nodular liver, evidence of portal hypertension)
    • Clinical signs of cirrhosis (gastroesophageal varices, ascites, hepatic encephalopathy)
    • Vibration controlled transient elastography (VCTE, specifically Fibroscan, which is available in all participating sites) with liver stiffness >12.5kPa or magnetic resonance elastography >5.0 kPa

  2. High Risk of Liver Cancer: This will be defined by one or more of the following:

    • Current HCV infection (detectable HCV RNA)
    • FIB-4 score 3.25, within 6 months of randomization
    • Estimated annual HCC incidence >2.5%, within 6 months of randomization, calculated by VA-specific models that the investigators developed (available on the national VA ALD Dashboard and at www.hccrisk.com).
  3. Age 18-75
  4. Able to provide informed consent

Exclusion Criteria:

  1. Prior diagnosis or of HCC
  2. Current suspicion of HCC
  3. Prior receipt of organ transplantation
  4. Currently listed for organ transplantation.
  5. Participation in a conflicting HCC screening trial
  6. Advanced liver dysfunction, defined by Child C Cirrhosis (CTP score 10), or MELD score >20, within 6 months prior to randomization
  7. Glomerular Filtration Rate (GFR) <30 ml/min
  8. Multiple comorbid conditions resulting in limited life expectancy, defined by a cirrhosis-specific comorbidity index (CirCom)112 score 3. Of note, early stage malignancies of the bladder, lung, or prostate will not be excluded.
  9. Estimated life expectancy <5 years as determined by the clinical judgement of the Study Investigator

  10. Contraindications to undergoing contrast-enhanced MRI:

    • Allergy to gadolinium-based contrast agents
    • MRI-incompatible implantable devices (e.g. pacemakers, defibrillators, resynchronization devices)
    • Implantable neurostimulation device
    • Implantable cochlear implant/ear implant
    • Drug infusion pumps (e.g. insulin pump, analgesic or chemotherapy pumps)
    • Metallic foreign bodies in or around the eye
    • Metallic fragments, such as bullets, shotgun pellets or shrapnel
    • Metallic body piercings that cannot be removed
    • Cerebral artery aneurysm clips
    • Severe claustrophobia
    • Unable to fit on MRI machine due to weight (weight >400lbs) or body habitus
  11. Inability to complete planned study visits (e.g. lives too far from VA, no transportation, etc.)
  12. Currently pregnant

Sites / Locations

  • VA Puget Sound Health Care System Seattle Division, Seattle, WA

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Other

Arm Label

Abdominal Ultrasound Screening with serum AFP

Abbreviated Magnetic Resonance Imaging with serum AFP

Arm Description

abdominal ultrasound (US)+serum alpha fetoprotein (AFP) every 6 months from the time of recruitment until the end of year 8

Abdominal aMRI+ serum AFP every 6 months from the time of recruitment until the end of year 8

Outcomes

Primary Outcome Measures

Hepatocellular Carcinoma Mortality
death due to liver cancer

Secondary Outcome Measures

Stage of Hepatocellular Carcinoma at diagnosis
Stage of Hepatocellular Carcinoma at time of diagnosis
Receipt of potentially curative treatments for Hepatocellular Carcinoma
Receipt of potentially curative treatments for Hepatocellular Carcinoma
Overall Survival
overall survival of liver cancer

Full Information

First Posted
August 1, 2022
Last Updated
October 16, 2023
Sponsor
VA Office of Research and Development
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1. Study Identification

Unique Protocol Identification Number
NCT05486572
Brief Title
Preventing Liver Cancer Mortality Through Imaging With Ultrasound vs. MRI
Acronym
PREMIUM
Official Title
CSP #2023 - Preventing Liver Cancer Mortality Through Imaging With Ultrasound vs. MRI (The PREMIUM Study)
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
November 15, 2023 (Anticipated)
Primary Completion Date
September 1, 2030 (Anticipated)
Study Completion Date
September 1, 2031 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
VA Office of Research and Development

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
The study is a randomized trial of two different screening methods for early detection of liver cancer in patients with cirrhosis of the liver. The goal of PREMIUM is to compare an abbreviated version of the diagnostic gold standard for HCC (aMRI) +AFP to the standard-of-care screening (US+AFP) in patients at high risk of developing HCC. The investigators hypothesize that HCC will be detected at earlier stages, allowing for more curative treatments and resulting in a reduction in HCC-related mortality.
Detailed Description
Study Design. The investigators propose to conduct a randomized controlled trial of screening for hepatocellular carcinoma (HCC) by ultrasound (US)+serum alpha fetoprotein (AFP) every 6 months (the current standard-of-care) versus abbreviated MRI (aMRI)+AFP every 6 months among patients with cirrhosis who have a high risk of HCC (estimated annual HCC risk >2.5%). Study Population. Patients ages 18-75 with cirrhosis (standard histologic, radiologic, or clinical criteria) of any etiology, with estimated annual HCC risk >2.5%. Exclusion Criteria: Prior HCC; Child C Cirrhosis (CTP score 10); MELD score >20; Listed for liver transplantation; Contra-indications to MRI; Comorbidities with limited life expectancy defined by a cirrhosis-specific comorbidity index (CirCom) score 3. Study Setting. 47 VA Medical Centers will recruit on average 100 patients/site over 3 years. These recruitment sites, which have already been identified, have adequate numbers of cirrhosis patients eligible for screening, a qualified hepatologist and radiologist to serve as local site investigators (LSIs), adequate MRI and US capacity, and access to a multidisciplinary liver tumor board (MLTB). Target Sample Size. N=2350 per group, total N=4700. Randomization. The randomization scheme will be random permuted with variable block size and will be stratified by medical center and MELD score. Intervention. Participants will be randomized in a 1:1 ratio to one of two screening arms: a. Abdominal aMRI+ serum AFP every 6 months, OR b. Abdominal US+ serum AFP every 6 months, from the time of recruitment until the end of study Year 8. The aMRI protocol will include only T1-weighted pre-contrast and dynamic contrast-enhanced images utilizing an extracellular gadolinium-based contrast agent. aMRI takes only ~15 minutes to perform. Enrollment will occur in Years 1-3, screening per protocol will continue through Year 8, and follow-up for mortality will continue through Year 8. Analysis and publication will be in Year 9. Primary Outcome. HCC-related mortality. Power Calculations. The study is powered to detect a minimum relative reduction in HCC-related mortality of 35% in the aMRI+AFP arm compared to the US+AFP arm, i.e. a reduction in cumulative HCC-related mortality at Year 8 from 7.1 per 100 patients in the US+AFP arm to 4.6 per 100 patients in the aMRI+AFP arm (absolute difference in HCC-related mortality of 2.5 per 100 patients), adjusted for dropout due to death from other causes or withdrawals, with power 88% and two-sided alpha 0.05.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Carcinoma, Hepatocellular, Cirrhosis
Keywords
hepatic, oncology, liver, chronic diseases; health services and systems, prospective, randomized, clinical trial, magnetic resonance imaging; ultrasonography, cirrhosis; liver cancer

7. Study Design

Primary Purpose
Prevention
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
4700 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Abdominal Ultrasound Screening with serum AFP
Arm Type
Active Comparator
Arm Description
abdominal ultrasound (US)+serum alpha fetoprotein (AFP) every 6 months from the time of recruitment until the end of year 8
Arm Title
Abbreviated Magnetic Resonance Imaging with serum AFP
Arm Type
Other
Arm Description
Abdominal aMRI+ serum AFP every 6 months from the time of recruitment until the end of year 8
Intervention Type
Other
Intervention Name(s)
Abbreviated Magnetic Resonance Imaging with serum AFP
Intervention Description
Abdominal aMRI+ serum AFP every 6 months from the time of recruitment until the end of year 8
Intervention Type
Other
Intervention Name(s)
Abdominal Ultrasound Screening with serum AFP
Intervention Description
abdominal ultrasound (US)+serum alpha fetoprotein (AFP) every 6 months from the time of recruitment until the end of year 8
Primary Outcome Measure Information:
Title
Hepatocellular Carcinoma Mortality
Description
death due to liver cancer
Time Frame
8 years
Secondary Outcome Measure Information:
Title
Stage of Hepatocellular Carcinoma at diagnosis
Description
Stage of Hepatocellular Carcinoma at time of diagnosis
Time Frame
8 years
Title
Receipt of potentially curative treatments for Hepatocellular Carcinoma
Description
Receipt of potentially curative treatments for Hepatocellular Carcinoma
Time Frame
8 years
Title
Overall Survival
Description
overall survival of liver cancer
Time Frame
8 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Cirrhosis due to any underlying etiology diagnosed by one or more of the following: Histology of liver biopsy Radiologic criteria (nodular liver, evidence of portal hypertension) Clinical signs of cirrhosis (gastroesophageal varices, ascites, hepatic encephalopathy) Vibration controlled transient elastography (VCTE, specifically Fibroscan, which is available in all participating sites) with liver stiffness >12.5kPa or magnetic resonance elastography >5.0 kPa High Risk of Liver Cancer: This will be defined by one or more of the following: Current HCV infection (detectable HCV RNA) FIB-4 score 3.25, within 6 months of randomization Estimated annual HCC incidence >2.5%, within 6 months of randomization, calculated by VA-specific models that the investigators developed (available on the national VA ALD Dashboard and at www.hccrisk.com). Age 18-75 Able to provide informed consent Exclusion Criteria: Prior diagnosis or of HCC Current suspicion of HCC Prior receipt of organ transplantation Currently listed for organ transplantation. Participation in a conflicting HCC screening trial Advanced liver dysfunction, defined by Child C Cirrhosis (CTP score 10), or MELD score >20, within 6 months prior to randomization Glomerular Filtration Rate (GFR) <30 ml/min Multiple comorbid conditions resulting in limited life expectancy, defined by a cirrhosis-specific comorbidity index (CirCom)112 score 3. Of note, early stage malignancies of the bladder, lung, or prostate will not be excluded. Estimated life expectancy <5 years as determined by the clinical judgement of the Study Investigator Contraindications to undergoing contrast-enhanced MRI: Allergy to gadolinium-based contrast agents MRI-incompatible implantable devices (e.g. pacemakers, defibrillators, resynchronization devices) Implantable neurostimulation device Implantable cochlear implant/ear implant Drug infusion pumps (e.g. insulin pump, analgesic or chemotherapy pumps) Metallic foreign bodies in or around the eye Metallic fragments, such as bullets, shotgun pellets or shrapnel Metallic body piercings that cannot be removed Cerebral artery aneurysm clips Severe claustrophobia Unable to fit on MRI machine due to weight (weight >400lbs) or body habitus Inability to complete planned study visits (e.g. lives too far from VA, no transportation, etc.) Currently pregnant
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
George N Ioannou, MD MS
Phone
(206) 277-3136
Email
George.Ioannou@va.gov
First Name & Middle Initial & Last Name or Official Title & Degree
Tamar H Taddei, MD
Phone
(203) 932-5711
Ext
5335
Email
tamar.taddei@va.gov
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
George N. Ioannou, MD MS
Organizational Affiliation
VA Puget Sound Health Care System Seattle Division, Seattle, WA
Official's Role
Study Chair
Facility Information:
Facility Name
VA Puget Sound Health Care System Seattle Division, Seattle, WA
City
Seattle
State/Province
Washington
ZIP/Postal Code
98108-1532
Country
United States
Facility Contact:
First Name & Middle Initial & Last Name & Degree
George N Ioannou, MD MS
Phone
206-277-3136
Email
George.Ioannou@va.gov
First Name & Middle Initial & Last Name & Degree
Tamar H Taddei, MD
Phone
(203) 932-5711
Ext
5335
Email
tamar.taddei@va.gov
First Name & Middle Initial & Last Name & Degree
George N. Ioannou, MD MS

12. IPD Sharing Statement

Plan to Share IPD
No

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Preventing Liver Cancer Mortality Through Imaging With Ultrasound vs. MRI

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