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Nonalcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease worldwide and is a major cause of cirrhosis and liver cancer in Western countries. Because of its close association with obesity and diabetes, most patients are seen by primary care physicians and endocrinologists rather than hepatologists. Previous studies have shown that NAFLD is under-recognized outside specialist settings. As a result, many patients are undiagnosed and not receiving specific treatments. With this background, 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 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.
This will be a parallel group, randomized controlled trial. 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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Intervention group | Experimental | 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. |
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| Control group | No Intervention | 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. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Simple fibrosis scores and electronic reminder messages | Diagnostic Test | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Action on Suspected Advanced Liver Fibrosis | Proportion of patients with high fibrosis scores who are referred for specialist care or further liver assessments | Within 1 year of the baseline visit |
| Measure | Description | Time Frame |
|---|---|---|
| Referral for Specialist Care | The proportion of patients referred for specialist care or further liver assessments, regardless of fibrosis score results | Within 1 year of the baseline visit |
| Inappropriate Referral for Specialist Care |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Vincent Wong, MD | Chinese University of Hong Kong | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Prince of Wales Hospital | Hong Kong | Hong Kong |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 37549979 | Derived | Zhang X, Yip TC, Wong GL, Leow WX, Liang LY, Lim LL, Li G, Ibrahim L, Lin H, Lai JCT, Chim AM, Chan HLY, Kong AP, Chan WK, Wong VW. Clinical care pathway to detect advanced liver disease in patients with type 2 diabetes through automated fibrosis score calculation and electronic reminder messages: a randomised controlled trial. Gut. 2023 Nov 24;72(12):2364-2371. doi: 10.1136/gutjnl-2023-330269. |
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Selected data may be shared with other researchers upon reasonable request.
1-5 years after the publication of the full paper.
Researchers with clear plans of collaboration and analysis
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| ID | Title | Description |
|---|---|---|
| FG000 | Intervention Group | 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. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Mar 27, 2023 |
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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.
| Within 1 year of the baseline visit |
| Confirmed Diagnosis of Advanced Liver Fibrosis | 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, (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. | Within 1 year of the baseline visit |
| FG001 | Control Group | 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. |
| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | Intervention Group | 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. |
| BG001 | Control Group | 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. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Action on Suspected Advanced Liver Fibrosis | Proportion of patients with high fibrosis scores who are referred for specialist care or further liver assessments | Patients with abnormal fibrosis scores | Posted | Count of Participants | Participants | Within 1 year of the baseline visit |
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| Secondary | Referral for Specialist Care | The proportion of patients referred for specialist care or further liver assessments, regardless of fibrosis score results | All participants | Posted | Count of Participants | Participants | Within 1 year of the baseline visit |
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| Secondary | Inappropriate Referral for Specialist Care | 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. | Patients with normal fibrosis scores | Posted | Count of Participants | Participants | Within 1 year of the baseline visit |
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| Secondary | Confirmed Diagnosis of Advanced Liver Fibrosis | 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, (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. | All participants | Posted | Count of Participants | Participants | Within 1 year of the baseline visit |
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1 year
Standard definitions were followed
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Intervention Group | 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. | 9 | 533 | 0 | 533 | 0 | 533 |
| EG001 | Control Group | 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. | 3 | 528 | 0 | 528 | 0 | 528 |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr Vincent Wong | The Chinese University of Hong Kong | +85235054205 | wongv@cuhk.edu.hk |
| Jun 14, 2024 |
| Prot_SAP_000.pdf |
| ID | Term |
|---|---|
| D065626 | Non-alcoholic Fatty Liver Disease |
| D003924 | Diabetes Mellitus, Type 2 |
| D005234 | Fatty Liver |
| ID | Term |
|---|---|
| D008107 | Liver Diseases |
| D004066 | Digestive System Diseases |
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D004700 | Endocrine System Diseases |
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| OG001 | Control Group | 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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| OG001 | Control Group | 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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