The Nijmegen-Leiden-Amsterdam 2-tiered Care Path Study

Non-Alcoholic Fatty Liver Disease Clinical Trial

— NLA2  

Official title:

A Care Path for the Detection of Advanced NAFLD-fibrosis: the Nijmegen-Leiden-Amsterdam 2-tiered Care Path Study - the NLA2 Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05712603
• Other study ID #: NL81357.018.22
• Status: Recruiting
• Start date: October 1, 2022
• Est. completion date: March 30, 2026

Study information

• Verified date: February 2023
• Source: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Contact: Stan Driessen, MD
• Phone: +31205667050
• Email: s.driessen2[@]amsterdamumc.nl
• Is FDA regulated: No
• Study type: Observational

Clinical 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. 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.

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 (

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 200
• Est. completion date: March 30, 2026
• Est. primary completion date: September 30, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Age = 18 years;
• Suspected by treating physician to suffer from a severe stage of NAFLD-fibrosis.

Exclusion Criteria:

• 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.

Related Conditions & MeSH terms

• Fatty Liver
• Liver Diseases
• Non-Alcoholic Fatty Liver Disease

Intervention

Diagnostic Test:
• FIB4-score
A score which estimates the risk for advanced liver fibrosis, based on: age, ALT, AST and thrombocytes
• Vibration controlled transient elastography
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 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).

Locations

Country	Name	City	State
Netherlands	Amsterdam UMC, location AMC	Amsterdam	Noord-holland
Netherlands	Leiden universitair medisch centrum	Leiden	Zuid-Holland
Netherlands	Radboudumc	Nijmegen	Gelderland

Sponsors (4)

Lead Sponsor	Collaborator
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)	Leiden University Medical Center, Maag Lever Darm Stichting, Radboud University Medical Center

Country where clinical trial is conducted

Netherlands, 

References & Publications (22)

Alexander 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. — View Citation

Crossan 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. — View Citation

Dulai 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. — View Citation

Eddowes PJ, Sasso M, Allison M, Tsochatzis E, Anstee QM, Sheridan D, Guha IN, Cobbold JF, Deeks JJ, Paradis V, Bedossa P, Newsome PN. Accuracy of FibroScan Controlled Attenuation Parameter and Liver Stiffness Measurement in Assessing Steatosis and Fibrosis in Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology. 2019 May;156(6):1717-1730. doi: 10.1053/j.gastro.2019.01.042. Epub 2019 Jan 25. — View Citation

Estes 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. — View Citation

Graupera I, Thiele M, Serra-Burriel M, Caballeria L, Roulot D, Wong GL, Fabrellas N, Guha IN, Arslanow A, Exposito C, Hernandez R, Aithal GP, Galle PR, Pera G, Wong VW, Lammert F, Gines P, Castera L, Krag A; Investigators of the LiverScreen Consortium. Low Accuracy of FIB-4 and NAFLD Fibrosis Scores for Screening for Liver Fibrosis in the Population. Clin Gastroenterol Hepatol. 2022 Nov;20(11):2567-2576.e6. doi: 10.1016/j.cgh.2021.12.034. Epub 2021 Dec 29. — View Citation

Harris 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. — View Citation

Lazarus 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. — View Citation

Marjot T, Moolla A, Cobbold JF, Hodson L, Tomlinson JW. Nonalcoholic Fatty Liver Disease in Adults: Current Concepts in Etiology, Outcomes, and Management. Endocr Rev. 2020 Jan 1;41(1):bnz009. doi: 10.1210/endrev/bnz009. — View Citation

Nabi O, Lacombe K, Boursier J, Mathurin P, Zins M, Serfaty L. Prevalence and Risk Factors of Nonalcoholic Fatty Liver Disease and Advanced Fibrosis in General Population: the French Nationwide NASH-CO Study. Gastroenterology. 2020 Aug;159(2):791-793.e2. doi: 10.1053/j.gastro.2020.04.048. Epub 2020 May 4. No abstract available. — View Citation

Ruissen 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. — View Citation

Siddiqui MS, Vuppalanchi R, Van Natta ML, Hallinan E, Kowdley KV, Abdelmalek M, Neuschwander-Tetri BA, Loomba R, Dasarathy S, Brandman D, Doo E, Tonascia JA, Kleiner DE, Chalasani N, Sanyal AJ; NASH Clinical Research Network. Vibration-Controlled Transient Elastography to Assess Fibrosis and Steatosis in Patients With Nonalcoholic Fatty Liver Disease. Clin Gastroenterol Hepatol. 2019 Jan;17(1):156-163.e2. doi: 10.1016/j.cgh.2018.04.043. Epub 2018 Apr 26. — View Citation

Srivastava 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. — View Citation

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. — View Citation

Sumida 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. — View Citation

Tapper 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. Erratum In: Am J Gastroenterol. 2016 Mar;111(3):446. — View Citation

Taylor 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. — View Citation

Tushuizen 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. — View Citation

Vali Y, Lee J, Boursier J, Spijker R, Loffler J, Verheij J, Brosnan MJ, Bocskei Z, Anstee QM, Bossuyt PM, Zafarmand MH; LITMUS systematic review team(dagger). Enhanced liver fibrosis test for the non-invasive diagnosis of fibrosis in patients with NAFLD: A systematic review and meta-analysis. J Hepatol. 2020 Aug;73(2):252-262. doi: 10.1016/j.jhep.2020.03.036. Epub 2020 Apr 8. — View Citation

Younossi 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. — View Citation

Younossi ZM, Golabi P, de Avila L, Paik JM, Srishord M, Fukui N, Qiu Y, Burns L, Afendy A, Nader F. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: A systematic review and meta-analysis. J Hepatol. 2019 Oct;71(4):793-801. doi: 10.1016/j.jhep.2019.06.021. Epub 2019 Jul 4. — View Citation

Younossi 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. — View Citation

* Note: There are 22 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Primary	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.	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	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.	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	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)	through study completion, an average of 1 year
Secondary	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;	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	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;	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	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;	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	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.	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	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.	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	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.	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.