Non-Alcoholic Fatty Liver DiseaseNLA2NCT05712603
The Nijmegen-Leiden-Amsterdam 2-tiered Care Path Study
An observational study of Non-Alcoholic Fatty Liver Disease, run by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) at 3 sites in Netherlands.
Trial summary
Non-alcoholic fatty liver disease (NAFLD) is a liver disease, caused by storage of fat in the liver. The most-important risk-factors are being overweight, and disorders in sugar and cholesterol handling of the body. On average does around 30% of the population worldwide have any signs of fatty liver. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Non-Alcoholic Fatty Liver Disease
- What is being tested?
- FIB4-score and Enhanced Liver Fibrosis test
- How many people
- 655 participants
- Where
- 3 sitesNetherlands
- Study dates
- 1 Oct 2022to 15 Oct 2024
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Patients will be recruited from three different academic medical centres in the Netherlands, namely Radboudumc, LUMC and Amsterdam UMC. Patients who are suspected of underlying severe NAFLD-fibrosis by their treating physician are eligible for inclusion in the study. This suspection will most often arise because of risk factors as obesity, diabetes type 2, hypercholesterolemia or metabolic syndrome, or proven heaptic steatosis because of an conventional ultrasound. Patients are referred from hospital specialists
Who may be able to join
- Age ≥ 18 years;
- Suspected by treating physician to suffer from a severe stage of NAFLD-fibrosis.
Who cannot join
- Previous diagnosis of advanced (≥F3) liver fibrosis;
- Any other known chronic liver disease (alcoholic steatohepatitis, hepatitis B, hepatitis C, autoimmune hepatitis, hemochromatosis, Wilsons disease, alpha-1-antitrypsin deficiency);
- Drugs that may cause drug-induced hepatic steatosis, (table provided elsewhere)
- Present excessive alcohol use, defined as > 2 units/day for women and > 3 units/day for men;
- A psychiatric, addictive or any other disorder that compromises the subject's ability to understand the study content and to give written informed consent for the participation in the study.
Trial locations and contacts
3 sites in 1 country.
Netherlands3 sites
Amsterdam UMC, location AMC
Amsterdam, North Holland, 1105AZ
Leiden universitair medisch centrum
Leiden, South Holland, 2333 ZA
Radboudumc
Nijmegen, Gelderland, 6525 GA
About this study
Official title: A Care Path for the Detection of Advanced NAFLD-fibrosis: the Nijmegen-Leiden-Amsterdam 2-tiered Care Path Study - the NLA2 Study
Non-alcoholic fatty liver disease (NAFLD) is a liver disease, caused by storage of fat in the liver. The most-important risk-factors are being overweight, and disorders in sugar and cholesterol handling of the body. On average does around 30% of the population worldwide have any signs of fatty liver. Most people will not get severe complaints as a result of their fatty liver. But in some of them, the fat storage will lead to hepatitis. This causes damage to the liver which can eventually lead to scarring of the liver, and in some patients to cirrhosis. This possibly can cause liver failure, liver cancer, an several complaints which reduce the quality of life. There are several tests which can help in detecting scarring of the liver. However, the scientific world still does not know well enough which test works best and if they perhaps might work better if they are used together. In this study these questions will be investigated in order to design a care path which does several tests consecutively. The goal is that this will make it possible to easily detect a severely diseased liver and that this will eventually help to detect patients earlier so they can be treated earlier and complications of the disease might be reduced. Moreover, is the goal that this study will lead to a decrease in unnecessary referrals to a hepatologist, resulting in a reduction in invasive diagnostic interventions. Hospital specialists who think that their patient might be at risk for advanced liver disease, can refer a patient to this study. Participants will go to the hospital for one study visit where several tests will be done which are designed to detect liver scarring. Depending on the results, a participant will be referred to a hepatologist for more extensive diagnostics or referred back to the referring specialist with advice for management of the disease.
Read the detailed description
Background of the study:
Non-alcoholic fatty liver disease (NAFLD) is a disease of alarmingly increasing prevalence. Progression along the NAFLD spectrum often goes unnoticed since it is often asymptomatic. Awareness among health care workers and implementation of care paths to detect progressing NAFLD stages are limited. Without clear guidance papers or robust care pathways for risk stratification, the current diagnostic approach for NAFLD is highly variable, leading to both underdiagnosis of advanced stages of disease, andunnecessary referrals for mild stages of disease. This calls for a comprehensive care path consisting of non-invasive alternatives to detect those patients with severe cases of NAFLD. Particularly the use of a sequential, two-tiered care path algorithm is promising as it has the ability to detect underlying advanced cases of fibrosis, and has previously been shown to be cost-effective. This was shown by dr. Ankur Srivastava, who designed a pathway consisting of FIB4-score and ELF-test that led to a reduction of unnecessary referrals to the hepatologist by 80%, whilst improving the detection of advanced fibrosis and cirrhosis 5- and 3-fold,respectively (8). In this study the investigation of several two-tiered sequential care path algorithms, comprised of the FIB4-score, VCTE and the ELF-test, for the detection of advanced stages of NAFLD-fibrosis is proposed: the Nijmegen-Leiden-AmsterdamNAFLD-NASH 2-tiered care path study: NLA2-study.
Objective of the study:
The aim of the study is to improve case finding of advanced cases of NAFLD (≥F3 fibrosis), whilst simultaneously reducing unnecessary referrals for mild cases (<F3 fibrosis). Additionally, the aim is to increase awareness of NAFLD, and NAFLD-related complications, and to assess the cost-effectiveness of the different proposed care paths compared to current regular care.
Study design:
This is a care innovation study, with an estimated duration of three years. The intend is to commence the study at three academic medical centres namely in Nijmegen, Leiden and Amsterdam, with the intention to include other non-academic hospitals after the initial roll-out. The study has both a prospective and a retrospective part. The prospective part consists of participants who are deemed by their treating specialist physician to be at risk of severe NASH fibrosis. Participants will be invited to attend a study visit.
This study visit will consist of, among others: anthropometric measurements, blood pressure measurement, blood sampling and VCTE. The diagnostic testing for potentially underlying advanced (≥F3) liver fibrosis consists of the FIB4-score, VCTE and the ELF-test. A blood sample will be stored for additional biomarker testing. Based on predefined cut-offs for the FIB4-score and liver stiffness measurement (LSM) (measured using VCTE), participants will be classified as being at low or high risk of advanced (≥F3)fibrosis (see figure 1). The ELF-test will be analysed in bulk and will thus not be used for risk assessment. Participants classified at low risk will remain under the care of their treating specialist. Participants classified at high risk of advanced (≥F3) fibrosis will be referred to a hepatologist. Read-outs of the electronic health records (EHR) of all participants will be performed at 24 months after inclusion in the study, an dat six months for those classified at high risk. Read-outs will be performed to assess the correctness of the risk assessment and subsequent referral to the hepatologist.
The three different sequential, two-tiered care path algorithms will be evaluated upon completion of the study. The diagnostic accuracy, defined as sensitivity, specificity, predictive values and AUROCs, of the three different care path algorithms will be calculated. The diagnostic performance will be expressed as the percentage of correct referrals and the percentage of unnecessary referrals of the different care path algorithms and the individual non-invasive tests, compared to regular care.
Study population:
The study population consists of adults (≥ 18 years old) who are suspected by their treating specialist to suffer from a severe stage of NAFLD-fibrosis. Exclusion criteria are, most notably, a previous diagnosis of advanced (≥F3) fibrosis, any other known chronic liver disease, use of drugs that may cause drug-induced steatosis, and present excessive alcohol use. The aim is to include 200 patients in analyses in total, of which 100 will be referred using the NLA2 study and 100 through regular care. The latter group will form the prospective comparator arm. This necessitates a 50% adherence rate of participating hospitals.
- Conditions
- Non-Alcoholic Fatty Liver Disease
- Being tested
- FIB4-score, Vibration controlled transient elastography, Enhanced Liver Fibrosis test
- Keywords
- Care path, Non-alcoholic Fatty Liver Disease, FIB4, FibroScan, ELF-test
- Medical subject headings
- Non-alcoholic Fatty Liver Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
FIB4-scoreDiagnostic test
A score which estimates the risk for advanced liver fibrosis, based on: age, ALT, AST and thrombocytes
Vibration controlled transient elastographyDiagnostic test
Also called VCTE
VCTE measures the speed of a mechanically generated shear wave across the liver to derive a liver stiffness measurement (LSM), a marker of hepatic fibrosis
Enhanced Liver Fibrosis testDiagnostic test
Also called ELF-test
The ELF-test is a non-invasive blood test that measures three direct markers of liver fibrosis: hyaluronic acid (HA), procollagen III amino-terminal peptide (PIIINP), and tissue inhibitor of matrix metalloproteinase 1 (TIMP-1).
| Study group | Role | What they receive |
|---|---|---|
| Prospective care path arm | Participants who enter the care path will make up the prospective care path arm.
In patients entering the care path three diagnostic tests for liver fibrosis will be performed. FIB4-score, Vibration controlled transient elastography and Enhanced Liver Fibrosis test Receives: Diagnostic Test: FIB4-score; Diagnostic Test: Vibration controlled transient elastography; Diagnostic Test: Enhanced Liver Fibrosis test | |
| Prospective arm of 'regular care' | Patients who are referred to the hepatologist in participating centers during the study period without using the care path (e.g. because of altered liver function tests for instance), will be the prospective 'regular care' arm | |
| Retrospective arm of 'regular care' | The investigators will do an data extraction of the electronic health records of patients referred to the hepatologist in the five years prior to the study. They will make up the retrospective comparative arm of regular care |
What is being measured
The primary outcome is the main question the study is designed to answer.
Diagnostic accuracy of the three different care paths to detect advanced fibrosis.
The diagnostic accuracy of the three different sequential care path algorithms to detect underlying advanced (≥F3) liver fibrosis, assessed using sensitivity, specificity, predictive values and area under the receiver characteristics (AUROC) curve
Measured: The time frame is based on the time between the study visit and the subsequent read-outs of the EHR, up to 24 months later
Diagnostic performance of the three different care paths to increase correct and decrease incorrect referrals.
The diagnostic performance of the three different sequential care path algorithms, defined as the increase in correct and the decrease in unnecessary referrals when using these care paths to detect underlying advanced (≥F3) NAFLD-fibrosis compared to regular care.
Measured: The time frame is based on the time between the study visit and the subsequent read-outs of the EHR, up to 24 months later
Secondary outcomes (8)
Cost effectiveness of the different diagnostic modalities/care path algorithms
The cost effectiveness of the different diagnostic modalities/care path algorithms compared to each other and to regular care.
Measured: The time frame is based on the time between the study visit and the subsequent read-outs of the EHR, up to 24 months later.
Number of patients coded for NAFLD before and after the study
Number of patients coded for NAFLD by physicians before and after initiation of the NLA2 study (measure of awareness)
Measured: through study completion, an average of 1 year
The diagnostic accuracy of the FIB4-score for detecting advanced fibrosis
The diagnostic accuracy of the FIB4-score for detecting underlying advanced (≥F3) liver fibrosis, using sensitivity, specificity, predictive values and AUROC-curves;
Measured: The time frame is based on the time between the study visit and the subsequent read-outs of the EHR, up to 24 months later.
The diagnostic accuracy of the ELF-test for detecting advanced fibrosis
The diagnostic accuracy of the ELF-test for detecting underlying advanced (≥F3) liver fibrosis, using sensitivity, specificity, predictive values and AUROC-curves;
Measured: The time frame is based on the time between the study visit and the subsequent read-outs of the EHR, up to 24 months later.
The diagnostic accuracy of VCTE for detecting advanced fibrosis
The diagnostic accuracy of VCTE for detecting underlying advanced (≥F3) liver fibrosis, using sensitivity, specificity, predictive values and AUROC-curves;
Measured: The time frame is based on the time between the study visit and the subsequent read-outs of the EHR, up to 24 months later.
Diagnostic performance of the FIB4-score to increase correct and decrease incorrect referrals.
The diagnostic performance of the FIB4-score, defined as the increase in correct and the decrease in unnecessary referrals when using this test to detect underlying advanced (≥F3) NAFLD-fibrosis compared to regular care.
Measured: The time frame is based on the time between the study visit and the subsequent read-outs of the EHR, up to 24 months later.
Diagnostic performance of VCTE to increase correct and decrease incorrect referrals.
The diagnostic performance of VCTE, defined as the increase in correct and the decrease in unnecessary referrals when using this test to detect underlying advanced (≥F3) NAFLD-fibrosis compared to regular care.
Measured: The time frame is based on the time between the study visit and the subsequent read-outs of the EHR, up to 24 months later.
Diagnostic performance of the ELF-test to increase correct and decrease incorrect referrals.
The diagnostic performance of the ELF-test, defined as the increase in correct and the decrease in unnecessary referrals when using this test to detect underlying advanced (≥F3) NAFLD-fibrosis compared to regular care.
Measured: The time frame is based on the time between the study visit and the subsequent read-outs of the EHR, up to 24 months later.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Feb 2023
- Study start1 Oct 2022
- Primary completion30 Jun 2024
- Study completion15 Oct 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (22)Papers the sponsor has linked to this study.
- Other trials for Non-Alcoholic Fatty Liver DiseaseStudies of the same condition, open and under way.
- More trials run by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 655 participants (actual)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Collaborators
- Maag Lever Darm Stichting, Radboud University Medical Center, Leiden University Medical Center
- Responsible party
- Principal investigator, Onno Holleboom, MD, PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
- Investigators
- Onno Holleboom, MD PhD, Principal investigator, Amsterdam UMC, location AMC
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05712603
- Sponsor's protocol ID
- NL81357.018.22
- Acronym
- NLA2
- Status last verified
- Oct 2024
- First submitted
- 19 Oct 2022
- Last updated
- 22 Oct 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Stols-Goncalves D, Hovingh GK, Nieuwdorp M, Holleboom AG. NAFLD and Atherosclerosis: Two Sides of the Same Dysmetabolic Coin? Trends Endocrinol Metab. 2019 Dec;30(12):891-902. doi: 10.1016/j.tem.2019.08.008. Epub 2019 Oct 17.
PubMed 31630897Tushuizen ME, Holleboom AG, Koot BGP, Blokzijl H, van Mil SWC, Koek GH. [Non-alcoholic fatty liver disease; a full-bodied epidemic]. Ned Tijdschr Geneeskd. 2020 Feb 27;164:D4096. Dutch.
PubMed 32267638Lazarus JV, Ekstedt M, Marchesini G, Mullen J, Novak K, Pericas JM, Roel E, Romero-Gomez M, Ratziu V, Tacke F, Cortez-Pinto H, Anstee QM; EASL International Liver Foundation NAFLD Policy Review Collaborators. A cross-sectional study of the public health response to non-alcoholic fatty liver disease in Europe. J Hepatol. 2020 Jan;72(1):14-24. doi: 10.1016/j.jhep.2019.08.027. Epub 2019 Sep 10.
PubMed 31518646Harris R, Harman DJ, Card TR, Aithal GP, Guha IN. Prevalence of clinically significant liver disease within the general population, as defined by non-invasive markers of liver fibrosis: a systematic review. Lancet Gastroenterol Hepatol. 2017 Apr;2(4):288-297. doi: 10.1016/S2468-1253(16)30205-9. Epub 2017 Feb 1.
PubMed 28404158Crossan C, Tsochatzis EA, Longworth L, Gurusamy K, Davidson B, Rodriguez-Peralvarez M, Mantzoukis K, O'Brien J, Thalassinos E, Papastergiou V, Burroughs A. Cost-effectiveness of non-invasive methods for assessment and monitoring of liver fibrosis and cirrhosis in patients with chronic liver disease: systematic review and economic evaluation. Health Technol Assess. 2015 Jan;19(9):1-409, v-vi. doi: 10.3310/hta19090.
PubMed 25633908Tapper EB, Sengupta N, Hunink MG, Afdhal NH, Lai M. Cost-Effective Evaluation of Nonalcoholic Fatty Liver Disease With NAFLD Fibrosis Score and Vibration Controlled Transient Elastography. Am J Gastroenterol. 2015 Sep;110(9):1298-304. doi: 10.1038/ajg.2015.241. Epub 2015 Aug 25.
PubMed 26303130Srivastava A, Gailer R, Tanwar S, Trembling P, Parkes J, Rodger A, Suri D, Thorburn D, Sennett K, Morgan S, Tsochatzis EA, Rosenberg W. Prospective evaluation of a primary care referral pathway for patients with non-alcoholic fatty liver disease. J Hepatol. 2019 Aug;71(2):371-378. doi: 10.1016/j.jhep.2019.03.033. Epub 2019 Apr 6.
PubMed 30965069Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016 Jul;64(1):73-84. doi: 10.1002/hep.28431. Epub 2016 Feb 22.
PubMed 26707365Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology. 2018 Jan;67(1):123-133. doi: 10.1002/hep.29466. Epub 2017 Dec 1.
PubMed 28802062Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M, George J, Bugianesi E. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018 Jan;15(1):11-20. doi: 10.1038/nrgastro.2017.109. Epub 2017 Sep 20.
PubMed 28930295Ruissen MM, Mak AL, Beuers U, Tushuizen ME, Holleboom AG. Non-alcoholic fatty liver disease: a multidisciplinary approach towards a cardiometabolic liver disease. Eur J Endocrinol. 2020 Sep;183(3):R57-R73. doi: 10.1530/EJE-20-0065.
PubMed 32508312Taylor RS, Taylor RJ, Bayliss S, Hagstrom H, Nasr P, Schattenberg JM, Ishigami M, Toyoda H, Wai-Sun Wong V, Peleg N, Shlomai A, Sebastiani G, Seko Y, Bhala N, Younossi ZM, Anstee QM, McPherson S, Newsome PN. Association Between Fibrosis Stage and Outcomes of Patients With Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis. Gastroenterology. 2020 May;158(6):1611-1625.e12. doi: 10.1053/j.gastro.2020.01.043. Epub 2020 Feb 4.
PubMed 32027911Dulai PS, Singh S, Patel J, Soni M, Prokop LJ, Younossi Z, Sebastiani G, Ekstedt M, Hagstrom H, Nasr P, Stal P, Wong VW, Kechagias S, Hultcrantz R, Loomba R. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic review and meta-analysis. Hepatology. 2017 May;65(5):1557-1565. doi: 10.1002/hep.29085. Epub 2017 Mar 31.
PubMed 28130788Sumida Y, Nakajima A, Itoh Y. Limitations of liver biopsy and non-invasive diagnostic tests for the diagnosis of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J Gastroenterol. 2014 Jan 14;20(2):475-85. doi: 10.3748/wjg.v20.i2.475.
PubMed 24574716Alexander M, Loomis AK, van der Lei J, Duarte-Salles T, Prieto-Alhambra D, Ansell D, Pasqua A, Lapi F, Rijnbeek P, Mosseveld M, Avillach P, Egger P, Dhalwani NN, Kendrick S, Celis-Morales C, Waterworth DM, Alazawi W, Sattar N. Non-alcoholic fatty liver disease and risk of incident acute myocardial infarction and stroke: findings from matched cohort study of 18 million European adults. BMJ. 2019 Oct 8;367:l5367. doi: 10.1136/bmj.l5367.
PubMed 31594780
Study at a glance
From the registry record, last updated by the sponsor on 22 Oct 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Care Path for the Detection of Advanced NAFLD-fibrosis: the Nijmegen-Leiden-Amsterdam 2-tiered Care Path Study - the NLA2 Study
- ClinicalTrials.gov ID
- NCT05712603
- Acronym / sponsor ID
- NLA2 / NL81357.018.22
- Conditions
- Non-Alcoholic Fatty Liver Disease
- Keywords
- Care path, Non-alcoholic Fatty Liver Disease, FIB4, FibroScan, ELF-test
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 655 participants (actual)
- Lead sponsor
- Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)University, hospital or other
- Collaborators
- Maag Lever Darm Stichting, Radboud University Medical Center, Leiden University Medical Center
- Study start
- 1 Oct 2022 (actual)
- Primary completion
- 30 Jun 2024 (actual)
- Study completion
- 15 Oct 2024 (actual)
- First posted
- 3 Feb 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Non-alcoholic fatty liver disease (NAFLD) is a liver disease, caused by storage of fat in the liver. The most-important risk-factors are being overweight, and disorders in sugar and cholesterol handling of the body. On average does around 30% of the population worldwide have any signs of fatty liver. Most people will not get severe complaints as a result of their fatty liver. But in some of them, the fat storage will lead to hepatitis. This causes damage to the liver which can eventually lead to scarring of the liver, and in some patients to cirrhosis. This possibly can cause liver failure, liver cancer, an several complaints which reduce the quality of life. There are several tests which can help in detecting scarring of the liver. However, the scientific world still does not know well enough which test works best and if they perhaps might work better if they are used together. In this study these questions will be investigated in order to design a care path which does several tests consecutively. The goal is that this will make it possible to easily detect a severely diseased liver and that this will eventually help to detect patients earlier so they can be treated earlier and complications of the disease might be reduced. Moreover, is the goal that this study will lead to a decrease in unnecessary referrals to a hepatologist, resulting in a reduction in invasive diagnostic interventions. Hospital specialists who think that their patient might be at risk for advanced liver disease, can refer a patient to this study. Participants will go to the hospital for one study visit where several tests will be done which are designed to detect liver scarring. Depending on the results, a participant will be referred to a hepatologist for more extensive diagnostics or referred back to the referring specialist with advice for management of the disease.
Detailed description
Background of the study:
Non-alcoholic fatty liver disease (NAFLD) is a disease of alarmingly increasing prevalence. Progression along the NAFLD spectrum often goes unnoticed since it is often asymptomatic. Awareness among health care workers and implementation of care paths to detect progressing NAFLD stages are limited. Without clear guidance papers or robust care pathways for risk stratification, the current diagnostic approach for NAFLD is highly variable, leading to both underdiagnosis of advanced stages of disease, andunnecessary referrals for mild stages of disease. This calls for a comprehensive care path consisting of non-invasive alternatives to detect those patients with severe cases of NAFLD. Particularly the use of a sequential, two-tiered care path algorithm is promising as it has the ability to detect underlying advanced cases of fibrosis, and has previously been shown to be cost-effective. This was shown by dr. Ankur Srivastava, who designed a pathway consisting of FIB4-score and ELF-test that led to a reduction of unnecessary referrals to the hepatologist by 80%, whilst improving the detection of advanced fibrosis and cirrhosis 5- and 3-fold,respectively (8). In this study the investigation of several two-tiered sequential care path algorithms, comprised of the FIB4-score, VCTE and the ELF-test, for the detection of advanced stages of NAFLD-fibrosis is proposed: the Nijmegen-Leiden-AmsterdamNAFLD-NASH 2-tiered care path study: NLA2-study.
Objective of the study:
The aim of the study is to improve case finding of advanced cases of NAFLD (≥F3 fibrosis), whilst simultaneously reducing unnecessary referrals for mild cases (<F3 fibrosis). Additionally, the aim is to increase awareness of NAFLD, and NAFLD-related complications, and to assess the cost-effectiveness of the different proposed care paths compared to current regular care.
Study design:
This is a care innovation study, with an estimated duration of three years. The intend is to commence the study at three academic medical centres namely in Nijmegen, Leiden and Amsterdam, with the intention to include other non-academic hospitals after the initial roll-out. The study has both a prospective and a retrospective part. The prospective part consists of participants who are deemed by their treating specialist physician to be at risk of severe NASH fibrosis. Participants will be invited to attend a study visit.
This study visit will consist of, among others: anthropometric measurements, blood pressure measurement, blood sampling and VCTE. The diagnostic testing for potentially underlying advanced (≥F3) liver fibrosis consists of the FIB4-score, VCTE and the ELF-test. A blood sample will be stored for additional biomarker testing. Based on predefined cut-offs for the FIB4-score and liver stiffness measurement (LSM) (measured using VCTE), participants will be classified as being at low or high risk of advanced (≥F3)fibrosis (see figure 1). The ELF-test will be analysed in bulk and will thus not be used for risk assessment. Participants classified at low risk will remain under the care of their treating specialist. Participants classified at high risk of advanced (≥F3) fibrosis will be referred to a hepatologist. Read-outs of the electronic health records (EHR) of all participants will be performed at 24 months after inclusion in the study, an dat six months for those classified at high risk. Read-outs will be performed to assess the correctness of the risk assessment and subsequent referral to the hepatologist.
The three different sequential, two-tiered care path algorithms will be evaluated upon completion of the study. The diagnostic accuracy, defined as sensitivity, specificity, predictive values and AUROCs, of the three different care path algorithms will be calculated. The diagnostic performance will be expressed as the percentage of correct referrals and the percentage of unnecessary referrals of the different care path algorithms and the individual non-invasive tests, compared to regular care.
Study population:
The study population consists of adults (≥ 18 years old) who are suspected by their treating specialist to suffer from a severe stage of NAFLD-fibrosis. Exclusion criteria are, most notably, a previous diagnosis of advanced (≥F3) fibrosis, any other known chronic liver disease, use of drugs that may cause drug-induced steatosis, and present excessive alcohol use. The aim is to include 200 patients in analyses in total, of which 100 will be referred using the NLA2 study and 100 through regular care. The latter group will form the prospective comparator arm. This necessitates a 50% adherence rate of participating hospitals.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Prospective care path arm | – | Diagnostic Test: FIB4-score, Diagnostic Test: Vibration controlled transient elastography, Diagnostic Test: Enhanced Liver Fibrosis testParticipants who enter the care path will make up the prospective care path arm. In patients entering the care path three diagnostic tests for liver fibrosis will be performed. FIB4-score, Vibration controlled transient elastography and Enhanced Liver Fibrosis test |
| Prospective arm of 'regular care' | – | –Patients who are referred to the hepatologist in participating centers during the study period without using the care path (e.g. because of altered liver function tests for instance), will be the prospective 'regular care' arm |
| Retrospective arm of 'regular care' | – | –The investigators will do an data extraction of the electronic health records of patients referred to the hepatologist in the five years prior to the study. They will make up the retrospective comparative arm of regular care |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Patients will be recruited from three different academic medical centres in the Netherlands, namely Radboudumc, LUMC and Amsterdam UMC. Patients who are suspected of underlying severe NAFLD-fibrosis by their treating physician are eligible for inclusion in the study. This suspection will most often arise because of risk factors as obesity, diabetes type 2, hypercholesterolemia or metabolic syndrome, or proven heaptic steatosis because of an conventional ultrasound. Patients are referred from hospital specialists
Key inclusion criteria (2 listed)
- Age ≥ 18 years;
- Suspected by treating physician to suffer from a severe stage of NAFLD-fibrosis.
Key exclusion criteria (5 listed)
- Previous diagnosis of advanced (≥F3) liver fibrosis;
- Any other known chronic liver disease (alcoholic steatohepatitis, hepatitis B, hepatitis C, autoimmune hepatitis, hemochromatosis, Wilsons disease, alpha-1-antitrypsin deficiency);
- Drugs that may cause drug-induced hepatic steatosis, (table provided elsewhere)
- Present excessive alcohol use, defined as > 2 units/day for women and > 3 units/day for men;
- A psychiatric, addictive or any other disorder that compromises the subject's ability to understand the study content and to give written informed consent for the participation in the study.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| FIB4-scoreA score which estimates the risk for advanced liver fibrosis, based on: age, ALT, AST and thrombocytes | Diagnostic test | Prospective care path arm |
| Vibration controlled transient elastographyAlso: VCTEVCTE measures the speed of a mechanically generated shear wave across the liver to derive a liver stiffness measurement (LSM), a marker of hepatic fibrosis | Diagnostic test | Prospective care path arm |
| Enhanced Liver Fibrosis testAlso: ELF-testThe ELF-test is a non-invasive blood test that measures three direct markers of liver fibrosis: hyaluronic acid (HA), procollagen III amino-terminal peptide (PIIINP), and tissue inhibitor of matrix metalloproteinase 1 (TIMP-1). | Diagnostic test | Prospective care path arm |
Primary outcome
Diagnostic accuracy of the three different care paths to detect advanced fibrosis.
Time frame: The time frame is based on the time between the study visit and the subsequent read-outs of the EHR, up to 24 months later
The diagnostic accuracy of the three different sequential care path algorithms to detect underlying advanced (≥F3) liver fibrosis, assessed using sensitivity, specificity, predictive values and area under the receiver characteristics (AUROC) curve
Diagnostic performance of the three different care paths to increase correct and decrease incorrect referrals.
Time frame: The time frame is based on the time between the study visit and the subsequent read-outs of the EHR, up to 24 months later
The diagnostic performance of the three different sequential care path algorithms, defined as the increase in correct and the decrease in unnecessary referrals when using these care paths to detect underlying advanced (≥F3) NAFLD-fibrosis compared to regular care.
8 secondary outcomes
Cost effectiveness of the different diagnostic modalities/care path algorithms
Time frame: The time frame is based on the time between the study visit and the subsequent read-outs of the EHR, up to 24 months later.
Number of patients coded for NAFLD before and after the study
Time frame: through study completion, an average of 1 year
The diagnostic accuracy of the FIB4-score for detecting advanced fibrosis
Time frame: The time frame is based on the time between the study visit and the subsequent read-outs of the EHR, up to 24 months later.
The diagnostic accuracy of the ELF-test for detecting advanced fibrosis
Time frame: The time frame is based on the time between the study visit and the subsequent read-outs of the EHR, up to 24 months later.
The diagnostic accuracy of VCTE for detecting advanced fibrosis
Time frame: The time frame is based on the time between the study visit and the subsequent read-outs of the EHR, up to 24 months later.
Diagnostic performance of the FIB4-score to increase correct and decrease incorrect referrals.
Time frame: The time frame is based on the time between the study visit and the subsequent read-outs of the EHR, up to 24 months later.
Diagnostic performance of VCTE to increase correct and decrease incorrect referrals.
Time frame: The time frame is based on the time between the study visit and the subsequent read-outs of the EHR, up to 24 months later.
Diagnostic performance of the ELF-test to increase correct and decrease incorrect referrals.
Time frame: The time frame is based on the time between the study visit and the subsequent read-outs of the EHR, up to 24 months later.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Oct 2024.
- Background: PubMed 31630897Stols-Goncalves D, Hovingh GK, Nieuwdorp M, Holleboom AG. NAFLD and Atherosclerosis: Two Sides of the Same Dysmetabolic Coin? Trends Endocrinol Metab. 2019 Dec;30(12):891-902. doi: 10.1016/j.tem.2019.08.008. Epub 2019 Oct 17.
- Background: PubMed 32267638Tushuizen ME, Holleboom AG, Koot BGP, Blokzijl H, van Mil SWC, Koek GH. [Non-alcoholic fatty liver disease; a full-bodied epidemic]. Ned Tijdschr Geneeskd. 2020 Feb 27;164:D4096. Dutch.
- Background: PubMed 31518646Lazarus JV, Ekstedt M, Marchesini G, Mullen J, Novak K, Pericas JM, Roel E, Romero-Gomez M, Ratziu V, Tacke F, Cortez-Pinto H, Anstee QM; EASL International Liver Foundation NAFLD Policy Review Collaborators. A cross-sectional study of the public health response to non-alcoholic fatty liver disease in Europe. J Hepatol. 2020 Jan;72(1):14-24. doi: 10.1016/j.jhep.2019.08.027. Epub 2019 Sep 10.
- Background: PubMed 28404158Harris R, Harman DJ, Card TR, Aithal GP, Guha IN. Prevalence of clinically significant liver disease within the general population, as defined by non-invasive markers of liver fibrosis: a systematic review. Lancet Gastroenterol Hepatol. 2017 Apr;2(4):288-297. doi: 10.1016/S2468-1253(16)30205-9. Epub 2017 Feb 1.
- Background: PubMed 25633908Crossan C, Tsochatzis EA, Longworth L, Gurusamy K, Davidson B, Rodriguez-Peralvarez M, Mantzoukis K, O'Brien J, Thalassinos E, Papastergiou V, Burroughs A. Cost-effectiveness of non-invasive methods for assessment and monitoring of liver fibrosis and cirrhosis in patients with chronic liver disease: systematic review and economic evaluation. Health Technol Assess. 2015 Jan;19(9):1-409, v-vi. doi: 10.3310/hta19090.
- Background: PubMed 26303130Tapper EB, Sengupta N, Hunink MG, Afdhal NH, Lai M. Cost-Effective Evaluation of Nonalcoholic Fatty Liver Disease With NAFLD Fibrosis Score and Vibration Controlled Transient Elastography. Am J Gastroenterol. 2015 Sep;110(9):1298-304. doi: 10.1038/ajg.2015.241. Epub 2015 Aug 25.
- Background: PubMed 30965069Srivastava A, Gailer R, Tanwar S, Trembling P, Parkes J, Rodger A, Suri D, Thorburn D, Sennett K, Morgan S, Tsochatzis EA, Rosenberg W. Prospective evaluation of a primary care referral pathway for patients with non-alcoholic fatty liver disease. J Hepatol. 2019 Aug;71(2):371-378. doi: 10.1016/j.jhep.2019.03.033. Epub 2019 Apr 6.
- Background: PubMed 26707365Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016 Jul;64(1):73-84. doi: 10.1002/hep.28431. Epub 2016 Feb 22.
- Background: PubMed 28802062Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology. 2018 Jan;67(1):123-133. doi: 10.1002/hep.29466. Epub 2017 Dec 1.
- Background: PubMed 28930295Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M, George J, Bugianesi E. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018 Jan;15(1):11-20. doi: 10.1038/nrgastro.2017.109. Epub 2017 Sep 20.
- Background: PubMed 32508312Ruissen MM, Mak AL, Beuers U, Tushuizen ME, Holleboom AG. Non-alcoholic fatty liver disease: a multidisciplinary approach towards a cardiometabolic liver disease. Eur J Endocrinol. 2020 Sep;183(3):R57-R73. doi: 10.1530/EJE-20-0065.
- Background: PubMed 32027911Taylor RS, Taylor RJ, Bayliss S, Hagstrom H, Nasr P, Schattenberg JM, Ishigami M, Toyoda H, Wai-Sun Wong V, Peleg N, Shlomai A, Sebastiani G, Seko Y, Bhala N, Younossi ZM, Anstee QM, McPherson S, Newsome PN. Association Between Fibrosis Stage and Outcomes of Patients With Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis. Gastroenterology. 2020 May;158(6):1611-1625.e12. doi: 10.1053/j.gastro.2020.01.043. Epub 2020 Feb 4.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Onno Holleboom, MD PhD principal investigator
Amsterdam UMC, location AMC
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Non-Alcoholic Fatty Liver Disease, run by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) at 3 sites in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 22 Oct 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Diagnostic accuracy of the three different care paths to detect advanced fibrosis. (time frame: The time frame is based on the time between the study visit and the subsequent read-outs of the EHR, up to 24 months later). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05712603, which also lists 22 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Oct 2024.