Clinical trial NCT05712603: The Nijmegen-Leiden-Amsterdam 2-tiered Care Path 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
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Non-Alcoholic Fatty Liver Disease
Keywords: Care path
Non-alcoholic Fatty Liver Disease
FIB4
FibroScan
ELF-test
Lead sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Sponsor class: OTHER
Collaborators: name: Maag Lever Darm Stichting
name: Radboud University Medical Center
name: Leiden University Medical Center
First posted: 2023-02-03
Enrollment: 655
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
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

Brief 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Diagnostic accuracy of the three different care paths to detect advanced fibrosis.
timeFrame: 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
measure: Diagnostic performance of the three different care paths to increase correct and decrease incorrect referrals.
timeFrame: 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:
measure: Cost effectiveness of the different diagnostic modalities/care path algorithms
timeFrame: 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.
measure: Number of patients coded for NAFLD before and after the study
timeFrame: through study completion, an average of 1 year
measure: The diagnostic accuracy of the FIB4-score for detecting advanced fibrosis
timeFrame: 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.
measure: The diagnostic accuracy of the ELF-test for detecting advanced fibrosis
timeFrame: 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.
measure: The diagnostic accuracy of VCTE for detecting advanced fibrosis
timeFrame: 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.
measure: Diagnostic performance of the FIB4-score to increase correct and decrease incorrect referrals.
timeFrame: 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.
measure: Diagnostic performance of VCTE to increase correct and decrease incorrect referrals.
timeFrame: 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.
measure: Diagnostic performance of the ELF-test to increase correct and decrease incorrect referrals.
timeFrame: 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.
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: Radboudumc
state: Gelderland
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC, location AMC
state: Noord-holland
city: Leiden
country: Netherlands
facility: Leiden universitair medisch centrum
state: Zuid-Holland
Study officials:
affiliation: Amsterdam UMC, location AMC
name: Onno Holleboom, MD PhD
role: PRINCIPAL_INVESTIGATOR
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