Identification of Fatty Liver With Advanced Fibrosis in Patients With Type 2 Diabetes Using Simple Fibrosis Scores and Electronic Reminder Messages: A Randomized Controlled Trial
Phase: NA
Conditions: Fatty Liver, Nonalcoholic, Diabetes Mellitus, Type 2
Sponsor: Chinese University of Hong Kong

NAFLD-NIT-RCT V1.1 dated 27 March 2023 
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Identification of fatty liver with advanced fibrosis in patients with type 2 diabetes using 
simple fibrosis scores and electronic reminder messages: A randomized controlled trial 
(Short title: NAFLD-NIT-RCT) 
 
Clinical study protocol 
 
 
Prepared by: 
Vincent Wong 
Professor 
Department of Medicine and Therapeutics 
The Chinese University of Hong Kong 
 
Version 1.1 
Date: 27 March 2023 
 
 

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1. BACKGROUND 
1.1 Importance of nonalcoholic fatty liver disease 
Nonalcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease 
worldwide. In Hong Kong, NAFLD affects 27% of the local adult population [1], and the annual 
incidence is 3.4% [2]. Nonalcoholic steatohepatitis (NASH), the more active form of NAFLD 
with hepatic necroinflammation and accelerated fibrosis, has already become the second 
leading indication for liver transplantation and the third leading cause of liver cancer in the 
United States [3]. On the other hand, NAFLD is largely asymptomatic. Compared with other 
chronic liver diseases, patients with liver cancer from NAFLD/NASH often present at a late 
stage when curative treatment cannot be offered [4]. Besides, several drugs have now entered 
phase 3 development for fibrotic NASH [5]. If successful, the first NASH drugs are expected to 
be available at the clinic in 1 to 2 years. Therefore, it is important to identify patients with 
advanced NAFLD for future treatment and liver cancer surveillance. 
 
1.2 High risk of severe NAFLD in patients with type 2 diabetes 
NAFLD is strongly associated with metabolic syndrome and insulin resistance. In particular, 
NAFLD is present in more than 50% of patients with type 2 diabetes [6]. Diabetes is also 
associated with the histological severity of NAFLD [7]. In a study of 6508 NAFLD patients from 
Japan, diabetes was associated with a 3-fold increase in the risk of liver cancer [8]. Recently, 
our group conducted a screening study in 1918 patients with type 2 diabetes using transient 
elastography (FibroScan) and showed that 18% had increased liver stiffness suspicious of 
advanced liver fibrosis (i.e. bridging fibrosis [F3] or cirrhosis [F4]) [9]. All these suggest that 
patients with type 2 diabetes represent a high-risk group worthy of case identification. 
However, there has been no agreed policy on how to identify patients with advanced liver 
disease. 
 
1.3 Non-invasive prediction of advanced fibrosis by prediction scores 
The severity of liver fibrosis is a key determinant of liver-related morbidity and mortality in 
NAFLD patients. In a meta-analysis of 1495 biopsy-proven NAFLD patients from 5 studies, the 
incidence of all-cause mortality was increased by 3.5-fold and 6.4-fold in patients with bridging 
fibrosis (F3) and cirrhosis (F4), respectively, compared with those without fibrosis [10]. It is 
therefore important to identify patients with advanced fibrosis for further monitoring and 
management. Although we demonstrated the role of transient elastography screening in 
patients with type 2 diabetes [9], the number of diabetic patients exceeds the capacity of most 
medical centers. Besides, since diabetic patients can develop many other complications, it is 
important to keep the diagnostic and referral process simple. 
 
Using liver histology as the reference standard, various groups have derived and validated 

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simple scores to predict advanced liver fibrosis [11]. These scores are calculated from routine 
clinical and laboratory parameters and have high applicability in different clinical settings. 
Although the scores are not as accurate as transient elastography or magnetic resonance 
elastography, they have high negative predictive values in excluding advanced fibrosis and are 
well suited for initial assessment [12, 13]. In our own study, the area under the receiver-
operating characteristics curve for detecting advanced fibrosis (F3-4) and cirrhosis (F4) was 
0.74 and 0.75 for the aspartate aminotransferase-to-platelet ratio index (APRI), 0.80 and 0.81 
for the Fibrosis-4 (FIB-4) index, and 0.75 and 0.80 for the NAFLD fibrosis score, respectively 
[13]. Importantly, patients with low fibrosis scores have very low risk of developing liver-
related morbidity and mortality during long-term follow-up [14, 15]. 
 
Among the published simple scores, the FIB-4 index and NAFLD fibrosis score have been 
consistently shown to be the most accurate in detecting advanced fibrosis by our group and 
others [12, 13]. We select the FIB-4 index and APRI as initial assessment in this study because 
we found that the NAFLD fibrosis score is increased in the majority of diabetic patients and is 
indiscriminating in this population (please see section on Preliminary Data for details). 
 
1.4 Care model based on fibrosis scores 
To facilitate efficient use of medical resource and identification of NAFLD patients at risk of 
future liver-related complications, we envision that the care model should be simple and 
convenient. Our center first promoted a care model to provide structured complications 
screening for patients with type 2 diabetes in the 1980s. At the diabetes center, patients 
undergo clinical assessment and laboratory tests to detect microvascular and macrovascular 
complications and check if they meet metabolic treatment targets. The care model has now 
extended to other hospitals in Hong Kong as well as other countries [16]. 
 
Since the calculation of liver fibrosis scores only require routine clinical and biochemical 
parameters, it would be easy to add them as one of the assessments for diabetic patients. We 
therefore propose including the fibrosis scores in diabetes complication screening and using 
electronic reminder message to suggest physicians to refer patients with elevated fibrosis 
scores for specialist care or further assessments. In the era of electronic health records, 
automatic reminder messages can improve identification of patients for appropriate screening 
and management [17]. 
 
2. AIMS 
We aim to test the hypothesis that the use of simple fibrosis scores as part of a diabetes 
complications screening program followed by electronic reminder messages is more effective 

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than usual care in prompting physicians to correctly identify patients with suspected NAFLD 
and advanced liver fibrosis for specialist referral or further liver assessment. Our secondary 
aim is to test the hypothesis that the use of fibrosis scores and electronic reminder messages 
can increase the number of patients with confirmed diagnosis of advanced liver fibrosis. 
 
3. STUDY DESIGN OVERVIEW 
This will be a parallel group, randomized controlled trial (Figure 1). Patients fulfilling the 
inclusion and exclusion criteria above will be randomized 1:1 to two groups. Randomization 
will be carried out through the use of computer-generated list of random numbers in variable 
blocks of 4 to 10. Concealment of group allocation will be achieved through putting the group 
allocation cards in consecutively-numbered and sealed envelopes. The patients and physicians 
will know that the patients are in the intervention group if they see the reminder messages. 
When they do not see a reminder message, there will not be a specific indicator of whether 
the patient is in the control group or in the intervention group but having low fibrosis scores. 
Furthermore, the outcome assessors will be blinded to the group assignment. 
 
For patients in the intervention group, we will calculate the fibrosis scores. For patients with 
increased fibrosis scores, we will type the following pop-up message in our electronic clinical 
management system: 
 
“This patient has high Fibrosis-4 index (and/or AST-to-platelet ratio index) of xxx suggestive 
of significant liver fibrosis. Please consider referring the patient to the hepatology clinic or 
arranging further test such as FibroScan.” 
 
The reminder message will pop up when physicians see the patient at the clinic and use the 
electronic clinical management system. The message will remain active for one year. Although 
the message is entered manually at this stage, the arrangement mimics an automated 
computer system. If the study results are positive, the next step is to modify the system to 
automate the process. 
 
Patients in the control group will undergo the same assessments as patients in the intervention 
group. Although physicians will have access to the raw liver biochemistry results and platelet 
count, the fibrosis score results will not be specifically shown, and there will be no electronic 
reminder messages regardless of the fibrosis scores. This is to mimic usual care when there is 
no dedicated care model for case identification. 
 

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4. PATIENTS 
We will recruit consecutive subjects from the Diabetes Mellitus and Endocrine Centre, Prince 
of Wales Hospital when they attend for diabetes complications screening. 
 
4.1 Inclusion criteria 
All subjects should fulfill all of the following: 
- 
Age 18-70 years 
- 
Having type 2 diabetes 
- 
Provided informed written consent 
 
4.2 Exclusion criteria 
Subjects having any of the following will be excluded from the study: 
- 
Type 1 diabetes 
- 
Already receiving specialist care by gastroenterologists or hepatologists 
- 
Current or past history of hepatocellular carcinoma or liver decompensation 
- 
Active malignancies other than hepatocellular carcinoma, unless in complete remission 
for more than 5 years 
 
Notably, although our primary focus is to identify patients with NAFLD and advanced liver 
fibrosis, we will not exclude patients with other chronic liver diseases such as chronic viral 
hepatitis or alcohol-related liver disease. In real life, although NAFLD is the most common 
chronic liver disease among diabetic patients, they can also have other liver diseases. It would 
also be meaningful to detect those diseases, especially if advanced fibrosis has already 
developed.  
 
5. STUDY ASSESSMENTS 
5.1 Clinical assessments 
At study inclusion, all patients will undergo the following assessments: 
- 
Record medical history including past medical history and drug history 
- 
Record smoking and alcohol consumption using a standard questionnaire 
- 
Measure blood pressure, body weight, body height and waist circumference; body mass 
index is calculated as body weight (kg) divided by body height (m) squared 
- 
Blood tests including liver biochemistry (including alanine aminotransferase [ALT], 
aspartate aminotransferase [AST] and gamma-glutamyl transpeptidase [GGT]), renal 
function test, fasting plasma glucose, hemoglobin A1c and lipids 
- 
Standard assessment for diabetic complications including spot urine for albumin-to-

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creatinine ratio for albuminuria, retinal photography for retinopathy, foot examination 
including monofilament and tuning fork test for peripheral neuropathy 
 
5.2 Fibrosis score 
In this study, we will calculate the FIB-4 index using the following formula: age x AST (U/l) / 
platelet count (x109/l) / √ALT (U/l) [18]. APRI is calculated as AST (/upper limit of normal) / 
platelet count (x109/l) x 100 [19]. Table 1 lists the cutoffs for the interpretation of the fibrosis 
scores, with age-specific adjustments for the FIB-4 index and NAFLD fibrosis score [20]. 
 
5.3 Diagnostic workup at the hepatology clinic 
Regardless of group assignment and fibrosis score results, diabetic patients referred to the 
hepatology clinic in this project will be seen within 12 weeks. We will perform history taking 
and physical examination to identify risk factors of chronic liver diseases. Viral hepatitis 
serology will be performed if not already done. The patients will then undergo transient 
elastography (FibroScan, Echosens, Paris, France) for liver stiffness measurement. Transient 
elastography will be performed by experienced operators under the training and instructions 
of the manufacturer [13]. The median of 10 liver stiffness measurements will be used to reflect 
the severity of liver fibrosis. Our center is equipped with the M probe and XL probe to cater 
for patients with different body built [21]; we will follow the machine’s automatic probe 
selection tool. We will discuss the option of liver biopsy with patients whose diagnosis is 
uncertain or liver stiffness is >10 kPa suspicious of advanced fibrosis [22].  
 
6. DATA ANALYSIS 
6.1 Primary outcome 
The primary outcome is the proportion of patients with high fibrosis scores who are referred 
for specialist care or further liver assessments within 1 year of the baseline visit. In this study, 
appropriate further liver assessments for advanced liver disease include transient 
elastography (FibroScan), shear wave elastography, acoustic radiation force impulse, magnetic 
resonance elastography, liver biopsy, and specific blood biomarkers of liver fibrosis such as 
FibroTest and FibroMeter. This primary outcome will address our primary aim to evaluate 
whether a care model comprising fibrosis score testing and electronic reminder messages can 
increase case identification and improve the diagnostic process. 
 
6.2 Secondary outcomes 
The following secondary outcomes will be analyzed: 
- 
The proportion of patients referred for specialist care or further liver assessments, 
regardless of fibrosis score results. 

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- 
The proportion of patients with low fibrosis scores who are referred for specialist care. 
Because NAFLD is highly prevalent and only a minority of patients have advanced fibrosis, 
referral of patients who will unlikely develop liver-related complications to specialists 
represents inefficient use of precious healthcare resource and should be minimized. This 
notion has major resource implications, and the current study will provide important 
information to guide healthcare policy. We recognize that physicians may have other 
reasons to refer patients for specialist care (e.g. newly diagnosed viral hepatitis). The 
reasons for referral will be recorded and reported. 
- 
The proportion of patients confirmed to have advanced fibrosis. In this study, a patient 
is considered to have confirmed advanced fibrosis if (1) liver stiffness measurement by 
transient elastography is >15 kPa [22], (2) a liver biopsy shows bridging fibrosis (F3) or 
cirrhosis (F4), (3) unequivocal radiological features of cirrhosis (cirrhosis with nodular 
appearance, splenomegaly, ascites or varices), or (4) clinical, radiological or endoscopic 
evidence of portal hypertension. In case of discrepant results, liver biopsy and 
unequivocal evidence of cirrhosis and/or portal hypertension will override the liver 
stiffness measurement results. 
 
6.3 Outcome ascertainment 
Two researchers will review the clinical records of all patients for evidence of specialist referral 
or arrangement of further liver assessments. They will also use the electronic clinical 
management system to look for new specialist clinic appointments and radiological test 
arrangements. The researchers will be blinded to the group assignment. In case of discrepant 
interpretation, a third assessor will study the case and discuss with the other two assessors to 
come up with a consensus on whether a patient has specialist referral, further liver 
assessments, and advanced fibrosis. 
 
6.4 Statistical analysis 
We will perform intention-to-treat analysis for all primary and secondary outcomes. All 
randomized patients will be analyzed for the outcomes. Patients who are lost to follow-up will 
be considered not to have specialist referral, further liver assessments, and confirmed 
advanced fibrosis. Statistical significance is taken as a two-sided p value of <0.05. 
 
Primary outcome 
The primary outcome includes patients with high fibrosis scores in both groups and is 
calculated as the number of patients with specialist referral or further liver assessments 
divided by the total number of patients. The proportions in the two study groups will be 
compared by chi-square test. 
 

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Secondary outcomes 
The following secondary outcomes will all be compared by chi-square test. 
- 
The proportion of patients with specialist referral or further liver assessments, regardless 
of fibrosis score results, is calculated as the number of patients with specialist referral or 
further liver assessments divided by the total number of patients. 
- 
Among patients with low fibrosis scores, the proportion of patients with inappropriate 
specialist referrals is calculated as the number of patients referred for specialist care 
divided by the total number of patients. 
- 
The proportion of patients with confirmed advanced fibrosis is calculated as the number 
of patients with confirmed advanced fibrosis divided by the total number of patients. 
 
6.5 Sample size calculation 
According to our preliminary data (see below), 33% of patients with type 2 diabetes had 
increased FIB-4 index suspicious of advanced fibrosis, and 10% had increased APRI suspicious 
of significant fibrosis. In our previous screening study using transient elastography, only 
around 10% of diabetic patients with advanced liver fibrosis were under specialist care [9]. To 
be conservative, we assume that 20% of patients with high fibrosis scores in the control group 
will be referred for specialist care or further liver assessments. We also decide that the care 
model would be clinically meaningful if it can at least increase the referral rate to 37% in the 
intervention group. To detect this difference at a 5% significance level and 80% power, we need 
107 patients with high fibrosis scores per group. Using a more conservative estimation of 25% 
of patients having increased fibrosis scores, a total of 856 patients is needed for this study. 
Assuming a dropout rate of 10%, the final sample size is 952 patients (476 per arm). The 
assumption on dropout rate is realistic as all patients should have been on regular follow-up 
and we will only be observing the referral pattern and linkage to care in 1 year. 
 
6.6 Preliminary data 
To facilitate sample size calculation and study design, we prospectively evaluated 612 patients 
who underwent diabetic complications screening at our center, of whom 599 had complete 
laboratory data for fibrosis score calculation. Elevated FIB-4 index, APRI and NAFLD fibrosis 
score was observed in 33%, 10% and 68% of patients, respectively. In previous studies by our 
group and others, the FIB-4 index and NAFLD fibrosis score had higher accuracy for advanced 
fibrosis than other simple scores when liver histology was used as the reference standard [12, 
13]. On the other hand, hyperglycemia is an important component of the NAFLD fibrosis score 
[14]. As a result, the majority of diabetic patients would have increased NAFLD fibrosis score, 
rendering this score indiscriminating and not suitable for the triage of diabetic patients. 
Therefore, the FIB-4 index and APRI are chosen as the initial assessment in this study. 
 

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7. ETHICS 
7.1 Ethics review 
The final study protocol, including the final version of the Informed Consent Form, must be 
approved in writing by the Joint The Chinese University of Hong Kong – New Territories East 
Cluster Clinical Research Ethics Committee (CUHK-NTEC CREC). The protocol must be re-
approved by the CREC annually. All subsequent protocol amendments must be approved by 
the CREC. 
 
7.2 Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP, applicable regulatory requirements 
and the CREC. 
 
7.3 Informed consent 
The investigator(s) will ensure that the subject is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of the study. The informed 
consent forms are available in traditional Chinese. Subjects must also be notified that they are 
free to discontinue from the study at any time. The subject should be given the opportunity 
to ask questions and allow time to consider the information provided. The subject’s signed 
and dated informed consent must be obtained before conducting any procedure specific for 
the study. The Principal Investigator must store the original, signed Informed Consent Forms. 
One copy of the signed Informed Consent Form must be given to the subject. If modifications 
are made according to local requirements, the new version has to be approved by the CREC. 
 
8. ADVERSE EVENT REPORTING 
The adverse event reporting period for this study is from signing the informed consent through 
1 year of follow-up. 
 
8.1 Adverse events 
An adverse event is any undesirable medical event occurring in the subject within the trial 
period, whether or not it is related to the study intervention. 
 
The severity of an adverse event is defined as: 
Mild: Transient symptoms, no interference with the subject’s daily activities 
Moderate: Marked symptoms, moderate interference with the subject’s daily activities 
Severe: 
Severe interference with the subject’s daily activities. 

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The relationship of an adverse event to the study intervention is defined as: 
Probable: Good reasons and sufficient documentation to assume a causal relationship 
Possible: A causal relationship is conceivable and cannot be dismissed 
Unlikely: The event is unlikely related to the study intervention 
 
A telephone enquiry hotline for reporting subject’s adverse events is available. The 
investigator will record all relevant information including signs and symptoms of the event, the 
onset time, the date of the event, the laboratory findings, concomitant drugs, and the final 
outcome. All adverse events will be followed up until we have reached a defined outcome of 
the event, which can be one of the followings: (1) recovered with sequelae (for chronic 
conditions), (2) recovered, or (3) the management of the adverse event is taken over by 
another physician when the study ends. 
 
A clinical laboratory adverse event is any clinical laboratory abnormality that suggests a 
disease and/or organ toxicity is of sufficient severity that requires active intervention (i.e. 
change of dose, discontinuation of drug, more frequent follow-up or further investigation). 
 
8.2 Serious adverse events 
A serious adverse event is an adverse event that results in one of the following outcomes: 
- 
Death 
- 
Life-threatening 
- 
In-patient hospitalization or prolongation of existing hospitalization 
- 
A persistent or significant disability or incapacity 
- 
A congenital anomaly or birth defect 
The definitions of causal relationship to study intervention are the same as those for adverse 
events. We have a 24-hour on-call system to handle serious adverse events. The investigator 
will assess and treat the subjects as soon as possible. A standard serious adverse event form 
will be used (provided by the CREC at http://intranet.ccter.cuhk.edu.hk/sae/) to report the 
events within 24 hours after acknowledgement. We will arrange unscheduled follow-up visits 
immediately or within 24 hours on receiving the subject’s self-report of serious adverse events 
after the subjects have been discharged or if the subject has already been admitted to the 
hospital. Our investigators will assess the subject within 24 hours. The study team will record 
all relevant information including signs and symptoms of the event, the onset time, the date 
of the event, the laboratory findings, concomitant drugs, and the final outcome. A follow-up 
serious adverse event form will be sent within 14 days after submitting the initial serious 
adverse event form. Serious adverse events related to the study drug will be followed up until 
the subject has “recovered”, “recovered with sequelae” or “died”. SAE reports will be sent to 

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our ethics committee. An unscheduled visit will be performed if subjects have to withdraw 
early from the study. 
 
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