Nottingham Community Liver Biomarkers Cohort

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ClinicalTrials.gov Identifier: NCT02037867

Recruitment Status : Recruiting

First Posted : January 16, 2014

Last Update Posted : February 8, 2019

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Sponsor:

Information provided by (Responsible Party):

University of Nottingham

Study Description

Brief Summary:

Deaths due to advanced liver scarring (liver cirrhosis) continue to increase, and liver disease is now the 3rd leading cause of premature death in the United Kingdom. The majority of liver disease is lifestyle related (alcohol, obesity and associated type 2 diabetes, injecting drug use) and therefore reversible if caught at a precirrhosis stage. However, current liver function blood tests are poor inadequate, and subsequently a large burden of liver disease is currently missed.

A variety of noninvasive liver biomarkers (blood and imaging tests) have been developed which identify liver disease accurately at earlier stages of scarring. The identification of liver disease in the community, where previous studies have discovered a large burden of previously unidentified but significant liver disease, is therefore a feasible place to develop new liver disease investigation pathways using these noninvasive markers.

In collaboration with the Department of Health, Nottingham University Hospitals have commenced a pilot community liver disease pathway in two General Practices in Nottingham in February 2012. Patients with liver risk factors (hazardous alcohol use, obesity or type 2 diabetes)are invited to take part in the pathway. Patients undergo a simple blood test (AST:ALT ratio and BARD score), with a high test result requiring referral for a liver stiffness scan (Fibroscan)which is performed in the community setting. High threshold scan values are reviewed by a consultant liver specialist in a community liver clinic. Preliminary findings show that the pathway accurately identifies patients with early liver scarring and previously unidentified significant liver disease. The participating General Practitioners have also noted a striking number of patients finally engaging in important lifestyle changes following pathway implementation. A second phase of the pilot pathway, in 2 Inner City General Practices with a total practice population of c.14,000 patients commenced in June 2013.

We have subsequently designed this cohort study, where pilot participants will be consented for follow up over a long period. We will assess future liver-related and cardiovascular events (including death), and perform qualitative patient interviews to assess the reasons for and persistence of lifestyle changes after liver disease investigation. We hypothesize that stratification of liver disease in the community will unearth a significant amount of previously undetected but significant chronic liver disease. Moreover, we will evaluate whether stratification of liver disease using these tests predicts future liver and cardiovascular disease and death, and whether stratification has an impact on patient's future lifestyle choices.

Condition or disease	Intervention/treatment
Chronic Liver Disease Alcohol Use Disorder Type 2 Diabetes Persistently Elevated ALT Obesity	Device: Fibrosis Biomarkers

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Detailed Description:

Objectives:

To establish a community based cohort with risk factors for liver disease and stratification for liver disease severity using non-invasive biomarkers.
To establish the incidence of liver and cardiovascular morbidity and mortality in a community cohort.
To explore the quantitative and qualitative indicators to potential alterations in patient lifestyle following stratification of liver disease to inform future intervention development.
To evaluate novel blood markers of liver fibrosis and cirrhosis on a large cohort of primary care patients

Study Configuration:

Longitudinal Cohort Study with long-term follow up

Setting:

Primary Care, Nottingham

Number of Participants:

Prospective and consecutive recruitment in the East Midlands - approximately 500 patients per annum over a 4 year cohort inception period. Total anticipated cohort size 2,000 participants.

Description of Interventions:

Serum blood sampling (AST:ALT ratio, and serum stored for future liver biomarker development)
Transient Elastography (Fibroscan)
Qualitative Interviews (limited to approximately 30 patients)
Consent to longitudinal data follow-up and approach for future lifestyle intervention trials - consenting patients will be tagged on MRIS database.

Duration of Study:

48 month cohort inception with long term longitudinal follow up of cardiovascular and liver related outcomes and mortality data.

Outcome Measures:

Incidence of liver (cirrhosis) and cardiovascular disease (symptomatic coronary or cerebrovascular disease).
All cause morbidity and mortality.
Quantitative and qualitative lifestyle measures (including body mass index, exercise levels, alcohol consumption).

Patients who decide to participate in the community cohort will not be required to perform any specific actions or attend study visits (unless for the reasons stated below). Usual clinical care (both liver-related and non-liver related) will continue during the study period.

Patients will consent to long term longitudinal data follow-up using the Medical Research Information Service (MRIS) database. All patients enrolled in the community cohort will be prospectively tagged on MRIS. In particular, the investigators will request individual patient alerts on MRIS concerning prevalent cardiovascular disease events (angina, myocardial infarction and stroke), liver cirrhosis and cause of death.

Patients will consent to undertake qualitative research to evaluate the process of community stratification. A purposeful sample of patients completing the community biomarkers pathway will be invited to participate in qualitative follow up of their experiences of the pathway and any subsequent lifestyle change. A researcher, trained in qualitative research methods, will perform a semi-structured interview, which will assess any lifestyle changes occurring following liver pathway stratification. Specifically, changes in alcohol consumption, diet and exercise will be explored and evaluated, with assessment of the relationship to liver pathway stratification (both investigation results and lifestyle advice offered during the pathway). Interviews will performed either face-to-face, in which case this will be performed at the Nottingham Digestive Diseases Biomedical Research Unit, or over the telephone - in all cases voice recording will occur to allow analysis of information provided. An example interview proforma to be utilized for these qualitative interviews has been provided separately.

Patients will be consented to donate biosamples (including blood and urine) to the Nottingham Health Sciences Biobank on inception into the cohort. An appointment will be made at the NIHR Nottingham Digestive Diseases Biomedical Research Unit for witnessed written consent and to allow donation of biosamples. Samples will be collected by trained research nurses, who also form part of the research team. These biosamples will be utilized for future research into novel biomarkers of liver and cardiovascular disease, including proteomics and metabonomics. Where participants do not agree to the future use of the samples they will be destroyed in accordance with the Human Tissue Act, 2004.

In the future, the investigators will plan trials assessing novel exercise and dietary interventions, and subsequent effects on patient lifestyle parameters and future cardiovascular risk. Patients forming the community cohort will consent for contact regarding these future trials; however individual trials will be subject to their own ethical approval and written consent.

Study Design

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Study Type :	Observational [Patient Registry]
Estimated Enrollment :	2000 participants
Observational Model:	Cohort
Time Perspective:	Prospective
Target Follow-Up Duration:	20 Years
Official Title:	The Stratification of Liver Disease in the Community Using Fibrosis Biomarkers
Study Start Date :	May 2013
Estimated Primary Completion Date :	May 2033
Estimated Study Completion Date :	May 2033

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Type 2 diabetes Alcohol use disorder

MedlinePlus related topics: Liver Diseases

U.S. FDA Resources

Groups and Cohorts

Group/Cohort	Intervention/treatment
Patients Patients identified with one of the below chronic liver disease risk factors and undergoing community liver disease stratification using fibrosis biomarkers: Hazardous alcohol use (>14 units per week in females, >21 units per week in males, alcohol AUDIT score >=8 or read code relevant to alcohol abuse on GP system) Type 2 Diabetes Obesity Persistently raised serum ALT level, negative liver serology, and absence of above 2 risk factors	Device: Fibrosis Biomarkers Liver disease stratification with liver stiffness scan (Transient Elastography) Analysis of diagnostic performance of serum fibrosis markers (as listed above) Whole blood samples obtained for DNA analysis Other Name: AST:ALT ratio, APRI, BARD score, ELF Score, FIB4, NAFLD Fibrosis Score,Transient Elastography

Group/Cohort

Intervention/treatment

Patients

Patients identified with one of the below chronic liver disease risk factors and undergoing community liver disease stratification using fibrosis biomarkers:

Hazardous alcohol use (>14 units per week in females, >21 units per week in males, alcohol AUDIT score >=8 or read code relevant to alcohol abuse on GP system)
Type 2 Diabetes
Obesity
Persistently raised serum ALT level, negative liver serology, and absence of above 2 risk factors

Device: Fibrosis Biomarkers

Liver disease stratification with liver stiffness scan (Transient Elastography) Analysis of diagnostic performance of serum fibrosis markers (as listed above) Whole blood samples obtained for DNA analysis

Other Name: AST:ALT ratio, APRI, BARD score, ELF Score, FIB4, NAFLD Fibrosis Score,Transient Elastography

Outcome Measures

Primary Outcome Measures :

Liver and cardiovascular-related mortality [ Time Frame: 20 years ]
Death recorded as resulting from cardiovascular or liver-related causes

Secondary Outcome Measures :

Liver Cirrhosis [ Time Frame: 20 years ]
Incidence of compensated and decompensated cirrhosis diagnosis during the study period.
Cardiovascular Disease [ Time Frame: 20 years ]
Incidence of cardiovascular disease events(defined as symptomatic coronary or cerebrovascular disease)during the study period.
All-cause mortality [ Time Frame: 20 years ]
Recording of any death during the study period

Biospecimen Retention: Samples With DNA

Serum, whole blood and urine samples stored a -80 degrees Celsius.

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No
Sampling Method:	Non-Probability Sample

Study Population

A Primary Care database search (Systmone, TPP)will be performed to identify patients eligible for study (see inclusion criteria) in the discrete patient populations.

Criteria

Inclusion Criteria:

Adult patients aged 18 years or over (male or female) with primary risk factor for liver disease:
- Hazardous alcohol use (>14 units/week for women, >21 units/week for men)
- Type 2 Diabetes
- Obesity
- Persistently elevated ALT with normal liver serology

Exclusion Criteria:

Active malignancy at study enrolment
Inability to provide informed consent for study enrolment
Known presence of histologically proven liver disease prior to pilot pathway participation

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02037867

Locations

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United Kingdom
NIHR Nottingham Digestive Diseases Biomedical Research Unit	Recruiting
Nottingham, Notts, United Kingdom, NG7 2UH
Contact: Neil Guha, MRCP, PhD 01159249924 ext 70609 neil.guha@nottingham.ac.uk
Contact: Rebecca Harris, BMedSci, BMBS 01159249924 ext 70616 rebecca.harris@nottingham.ac.uk
Principal Investigator: Neil Guha, MRCP, PhD
Sub-Investigator: David J Harman, BMedSci, BMBS, MRCP
Sub-Investigator: Guruprasad P Aithal, FRCP, PhD
Sub-Investigator: Stephen D Ryder, MRCP, PhD
Sub-Investigator: Martin W James, MRCP, PhD
Sub-Investigator: Emilie A Wilkes, MRCP, PhD
Sub-Investigator: Rebecca Harris, BMedSci, BMBS, MRCP
Sub-Investigator: Timothy R Card, MRCP, PhD
Sub-Investigator: Toby E Delahooke, MRCP, MD

Sponsors and Collaborators

University of Nottingham

Investigators

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Principal Investigator:	Neil Guha, MRCP, PhD	University of Nottingham

More Information

Additional Information:

Nottingham Digestive Disease Biomedical Research Unit This link exits the ClinicalTrials.gov site

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Tanajewski L, Harris R, Harman DJ, Aithal GP, Card TR, Gkountouras G, Berdunov V, Guha IN, Elliott RA. Economic evaluation of a community-based diagnostic pathway to stratify adults for non-alcoholic fatty liver disease: a Markov model informed by a feasibility study. BMJ Open. 2017 Jul 5;7(6):e015659. doi: 10.1136/bmjopen-2016-015659.

Harman DJ, Ryder SD, James MW, Jelpke M, Ottey DS, Wilkes EA, Card TR, Aithal GP, Guha IN. Direct targeting of risk factors significantly increases the detection of liver cirrhosis in primary care: a cross-sectional diagnostic study utilising transient elastography. BMJ Open. 2015 May 3;5(4):e007516. doi: 10.1136/bmjopen-2014-007516.

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Responsible Party:	University of Nottingham
ClinicalTrials.gov Identifier:	NCT02037867
Other Study ID Numbers:	13029 13/EM/0123 ( Other Identifier: Research Ethics Committee (East Midlands - Leicester) )
First Posted:	January 16, 2014 Key Record Dates
Last Update Posted:	February 8, 2019
Last Verified:	February 2019

Keywords provided by University of Nottingham:


alcohol type 2 diabetes ALT	abnormal liver enzymes hepatic fibrosis cirrhosis

Additional relevant MeSH terms:

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Liver Diseases Diabetes Mellitus, Type 2 Alcoholism Diabetes Mellitus Glucose Metabolism Disorders Metabolic Diseases	Endocrine System Diseases Digestive System Diseases Alcohol-Related Disorders Substance-Related Disorders Chemically-Induced Disorders Mental Disorders

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