The Liver Care Trial: Screening for liver disease in individuals attending treatment for alcohol use disorder - study protocol for a randomized controlled study

The Liver Care Trial: Screening for liver disease in individuals attending treatment for alcohol use disorder - study protocol for a randomized controlled study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The Liver Care Trial: Screening for liver disease in individuals attending treatment for alcohol use disorder - study protocol for a randomized controlled study Pernille Dahlin, Peter Jepsen, Line Molzen, Lone Galmstrup Madsen, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4609877/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 28 Oct, 2025 Read the published version in Trials → Version 1 posted 5 You are reading this latest preprint version Abstract Background Early diagnosis of alcohol-related liver disease (ALD) can improve survival if it leads to alcohol abstention or very light consumption. It is possible to screen for liver fibrosis, an asymptomatic condition of ALD that can lead to cirrhosis, by an easy and noninvasive approach called transient elastography. It has not yet been established whether screening for liver fibrosis reduces alcohol consumption among individuals with alcohol use disorders compared to usual treatment. In addition, it is important to address whether receiving a screening result indicating no ALD could lead to increased alcohol consumption (the certificate-of-health effect). This is a protocol for a study that aims to evaluate the efficacy of screening for liver fibrosis with transient elastography on alcohol use outcomes in individuals who are receiving treatment for alcohol use disorder in the community. Methods The study follows a randomized, controlled trial design (RCT) with concealed allocation in a 2:1 ratio to the intervention group or the control group. Blinded outcome assessments will be conducted for both parallel groups. A total of 408 patients will be randomized to receive both transient elastography and blood tests (intervention group, n = 272) or usual care consisting of a blood test (control group, n = 136). The primary outcome will be abstinence or light consumption (≤ 10 units per week, 1 unit = 12 g alcohol) throughout the last 30 days, as evaluated six months after randomization. Secondary outcomes include health-related quality of life and motivation to reduce alcohol intake. The “certificate-of-health effect” will be assessed by comparing abstinence or light alcohol consumption after six months between the screen-negative patients and the controls. Additionally, qualitative studies will explore the emotional impact of screening on participants’ and health professionals’ barriers to the implementation of screening. Discussion This study has the potential to offer important insights into the effect of screening for liver fibrosis on alcohol consumption among individuals who are attending treatment for alcohol use disorder. Furthermore, the study will provide insights into user and health professionals’ experiences related to screening. Trial registration ClinicalTrials.gov NCT05855031. Registered on the 20th of April 2023. Alcohol use disorder screening alcohol-related liver disease liver fibrosis outpatient alcohol treatment transient elastography liver stiffness measurement randomized trial Administrative information This protocol was written in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Studies (SPIRIT) guidelines (1) Note: The numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/). Title {1} The Liver Care Trial: Screening for liver fibrosis in individuals attending treatment for alcohol use disorder - study protocol for a randomized controlled study Trial registration {2a and 2b}. ClinicalTrials.gov. Unique Protocol identifier: NCT05855031. Date of registration: 20-04-2023 Protocol version {3} Version 2.0 - 05.01.2023 Funding {4} This trial is funded by The cross-regional pool for research in prevention ID: R201-A4451 and the Novo Nordisk Foundation ID: NF22OC0079565. Author details {5a} a Medical Department, Section of Gastroenterology and Hepatology, Zealand University Hospital, Køge, Denmark b Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark c Center for Clinical Research and Prevention, Frederiksberg University Hospital, Copenhagen, Denmark d Novavi Alcohol treatment centre Køge, Køge, Denmark e Institute for Clinical Medicine, University of Copenhagen f Palliative Care Unit, Copenhagen University Hospital – Hvidovre, Denmark g Section of Biostatistics, Department of Public Health, University of Copenhagen h Department of Clinical Research, Hvidovre University Hospital, Hvidovre, Denmark I Department of Health and Social Context, National Institute of Public Health, University of Southern Denmark, Denmark Name and contact information for the trial sponsor {5b} Danish Regions: Dampfærgevej 22, 2100 København Ø (DK). Phone number +45 3529 8100 The Novavi Foundation: Peter Bangs Vej 7A, Bygning 9 2. etage, 2000 Frederiksberg (DK). Phone number +45 3945 5455 The Novo Nordisk Foundation: Tuborg Havnevej 19, 2900 Hellerup (DK). Phone number + 45 3527 6600 Role of sponsor {5c} The funders have no role in research design, data collection, management, analysis, and interpretation of data; writing of the article or decision to publish. Moreover, the researchers in this project have no commitments to the funders. Introduction Background and rationale {6a} Alcohol-related liver disease (ALD) represents a significant global health challenge, contributing to an annual death toll of 500,000 individuals worldwide ( 2 , 3 ). This high number highlights the urgent need for effective prevention strategies to combat the consequences of ALD. Currently, the prognosis for individuals diagnosed with ALD remains poor, with a mortality risk of approximately 35% within the first year following diagnosis ( 4 ). This high mortality risk is likely caused by the late-stage detection of ALD, as ALD is often diagnosed when complications of liver failure have developed ( 5 ). For example, in Denmark, approximately 50% of patients have already developed cirrhosis with complications at the time of their ALD diagnosis ( 6 , 7 ). Survival in patients with ALD could potentially improve if ALD was detected before liver-related complications developed, and importantly, if this earlier detection of ALD led to a reduction in alcohol consumption and preferably complete abstinence ( 8 ). Fortunately, advances in technology have paved the way for earlier detection of ALD by screening with a simple and noninvasive technique known as transient elastography (FibroScan©) ( 9 ). Transient elastography can detect ALD before symptoms of liver disease appear. It remains uncertain whether screening for ALD before the emergence of health problems is sufficient to induce a reduction in alcohol consumption and improve the prognosis in individuals with high alcohol consumption. To date, there are no randomized controlled trials (RCTs) comparing transient elastography with usual care to evaluate the efficacy abstinence or light-controlled consumption ( 10 , 11 ). Individuals receiving alcohol treatment are a suitable study population to offer a screening for liver fibrosis since they are likely to be motivated to abstain from alcohol use, and due to their 10 years of abusive alcohol intake, they constitute a high-risk group for ALD according to the European Association of the Study of Liver Disease (EASL) ( 8 ) Observational studies have indicated that appropriate behavioural advice in the context of health problems motivates a reduction in alcohol consumption ( 12 – 14 ). However, whether screening for liver fibrosis leads to a better prognosis than usual care cannot be established by observational evidence; for this, we need an RCT ( 15 ). There is also concern regarding the potential negative consequences of receiving a normal screening result, a phenomenon termed the "certificate-of-health effect" ( 10 , 16 , 17 ). The "certificate-of-health effect" has been observed in a colorectal cancer screening study, where individuals with normal screening findings had more weight gain than did the control group at follow-up three years later ( 16 ). In individuals with alcohol use disorders, one could fear that a normal screening result indicating a healthy liver may inadvertently drive steady or even increased alcohol consumption. Psychologically, the offer of screening for ALD could cause anxiety about having or being at risk of a chronic life-threatening disease ( 18 ). False-negative results of liver stiffness measurements are very rare, and the false positive rate is approximately 7% ( 9 ); thus, some patients are wrongly mistaken for having chronic liver disease. On the other hand, screening for liver disease in individuals attending alcohol misuse treatment may lead to an experience of interest from the healthcare system rather than neglect ( 19 ). Hence, there is a need to explore the psychological effects of screening for ALD. Furthermore, the transition of clinical innovations into routine practice is often a slow process, often taking years for widespread adoption ( 20 , 21 ). Therefore, there is a need to understand the barriers to effectively integrating screening procedures into standard care if we are to improve outcomes for individuals seeking treatment for alcohol use disorders. Objectives {7} The primary objective of this study is to evaluate whether screening for liver fibrosis with transient elastography leads to a reduction in alcohol intake in individuals attending alcohol treatment with no prior history of liver disease. The primary outcome is “abstinence or light consumption” (≤ 10 units a week) 6 months after randomization. We will test the hypothesis that screening for liver fibrosis with transient elastography in individuals attending treatment for alcohol use disorders will increase the proportion of individuals who are abstinent or with light-controlled consumption by 15% percent points or more after six months of follow-up compared to usual care. We find that such a difference represents a clinically significant difference to highlight the effectiveness of the screening. Qualitative objectives We will investigate the experiences of participants in liver screening regarding its impact on their emotions and behavior and the reasons for nonparticipation for those who refuse to participate in the screening. Furthermore, we aim to elucidate the barriers and facilitators that health professionals face when implementing liver screening in clinical practice for individuals receiving treatment for alcohol use disorders. Health-economic impact We plan longer-term follow-up after 2–3 years to investigate the health-economic impact of screening for liver disease by transient elastography versus usual care on healthcare costs, quality-adjusted life years and employment. The data for these analyses will come from Danish nationwide registries. Trial design {8} The study is a multicentre, open-label, randomized, controlled trial of transient elastography screening versus usual care with a 2:1 allocation ratio and blinded evaluation of the primary outcome of abstinence or light consumption (≤ 10 units a week) in the last 30 days at the six-month follow-up. In addition, as mentioned above, two qualitative studies and one long-term follow-up study are planned. These are only described in section 18a. Methods: Participants, interventions and outcomes Study setting and usual care {9} Participants are recruited from two specialized alcohol outpatient treatment centres, Novavi Køge and Novavi Roskilde, in Denmark. Together, these centres serve approximately 350 individuals annually who are seeking treatment for alcohol use disorder. Novavi is a not-for-profit organization that runs open outpatient treatment facilities in the greater capital area of Denmark and has previously participated in several research studies (22,23). Novavi offers psychosocial treatment based on motivational interviewing and cognitive behavioural therapy, and if needed, in combination with pharmacological treatment for alcohol use disorder, in line with guideline recommendations (24). All Danish citizens have access to universal, tax-financed healthcare, including outpatient treatment for alcohol use disorder, so there is no out-of-pocket payment for those who seek treatment in Novavi’s facilities (25). Individuals seeking treatment for alcohol use disorder can be referred by general practitioners, hospital doctors or, most commonly, they can refer themselves. The intervention will be performed at the Department of Gastroenterology and Hepatology, Medical Department, Zealand University Hospital. Eligibility criteria {10} Participants must provide written, informed consent before any study procedures occur (Additional file 1). Participants are eligible for study participation if they attend community-based outpatient treatment for alcohol use disorder (International Classification of Disease, version 10: F10.2: alcohol dependence or F10.1: harmful alcohol use) at Novavi Køge or Novavi Roskilde and are > 18 years of age. The exclusion criteria are severe liver disease known by the participant or inability to speak Danish. Health Professionals performing the intervention are eligible if they had completed a 1-day course in motivational interviewing and had completed at least 20 supervised transient elastographies. Who will take informed consent? {26a} Physicians and alcohol therapists employed at Novavi alcohol treatment centre will inform eligible participants about the study orally and in writing. Participants sign an informed consent for study participation after the necessary reflection time. Additional consent provisions for collection and use of participant data and biological specimens {26b} n/a – No biological specimens will be collected. Interventions Explanation for the choice of comparators {6b} The comparison group, consisting of participants randomized as controls, will receive usual care provided at the alcohol treatment centre and will receive routine blood samples, including FIB-4 See Supplementary Table 1, Additional file 2 (26,27). The FIB-4 is a fibrosis index based on four factors and is a is a screening tool used for the initial screening of liver fibrosis (28). According to the EASL, blood testing with FIB-4 measurement is considered the current standard practice(26). However, we suspect that the use of FIB-4 is not widely implemented in current clinical practice. Therefore, the control group in this study will receive a more comprehensive offer than individuals undergoing alcohol treatment who typically do not have access to FIB-4 testing. Participants randomized as controls are offered the possibility of blood samples being collected on the patients’ own accord. Participants will be informed by a physician after blood sampling only if the blood samples indicate abnormalities. Intervention description {11a} The intervention consists of 1) transient elastography using FibroScan©, 2) clinical examination of weight, height and waist circumference, 3) routine blood sampling see Supplementary Table 1 Additional file 2, and 4) the results of the transient elastography delivered in the spirit of motivational interviewing, including a leaflet with description of alcohol-related diseases and the health-related benefits of cutting down (29). Liver stiffness will be measured using FibroScan©. FibroScan© (transient elastography) works by measuring shear wave velocity with an ultrasound probe. FibroScan© is used to assess liver stiffness, which is correlated with liver fibrosis. FibroScan© is safe, does not cause adverse events and is used in daily clinical practice. Liver fibrosis will be defined as a test result > 8.0 kPa with 10 successful measurements and an interquartile range (IQR) < 30% of the median (8). Participants will receive an explanation of the procedure and be required to fast for four hours before the appointment. If liver stiffness measured by the FibroScan© was not possible due to obesity, etc., the FIB-4 score will be used instead. The participant undergoing transient elastography will have the exact test result of the FibroScan© explained promptly by the healthcare professional performing the FibroScan© and whether this indicates liver fibrosis or not. Moreover, the results will be written on the leaflet about alcohol-related diseases. If the blood sample results are abnormal, a physician will contact the participant by phone. The intervention will be delivered by a healthcare professional trained in motivational interviewing with a semistructured manual developed by a certified motivational interviewing coach (Additional File 3). If the FibroScan© is <8 kPa, the response is “The liver is still soft”, whereas for those with a FibroScan© ≥ 8 kPa, it will be “This may be a sign that the liver has become firmer because it has been working over time and further investigations are necessary to find this out”. Criteria for discontinuing or modifying allocated interventions {11b} Patients may withdraw consent to participate in the trial at any time without any justification. If the FibroScan© or the FIB-4 index suggests liver fibrosis (FibroScan© > 8.0 kPa or FIB-4 ³ 1.30) or the blood samples reveal anaemia or vitamin deficiencies, the participant will be offered routine assessment for this at the hospital department where the study takes place. Strategies to improve adherence to interventions {11c} Researchers will contact participants by phone within days of enrolment to schedule a transient elastography appointment within four weeks (preferably 2). Up to 10 calls will be made within two weeks after enrolment, if needed. Relevant concomitant care permitted or prohibited during the trial {11d} The participants in the study are permitted to participate in other interventions during the time of the trial, such as examinations for liver disease. If a participant has an examination during the trial, it will be detected in the participant’s electronic medical record at the follow-up, and the type of examination will be reported. No concomitant care is prohibited during the trial. Provisions for post-trial care {30} Patients will receive continued care according to the standard procedures of Novavi centres during and after the end of the study. If the participants have been referred to the hospital department, the diagnostic investigation will proceed after the trial. Outcomes {12} Primary outcome: Alcohol abstinence or light consumption (≤ 10 units/week) throughout the last 30 days (yes/no) was assessed at the six-month follow-up, for evaluation of primary outcome see Supplementary Table 2 Additional File 2. Ten units of alcohol/week is the “sensible drinking limit” in Denmark (30), and alcohol consumption below this limit minimizes the risk of ALD (8). The secondary outcomes are heavy drinking days, perceived alcohol problems (AUDIT C score), motivation to reduce alcohol consumption, health-related quality of life (SF-12 v2) and stress management (PSS) (31–33) (Additional file 4). Heavy drinking increases the risk of ALD independently of average alcohol intake (34); a heavy drinking day is defined for men as consuming five or more drinks and for women as consuming 4 or more drinks (35) Other secondary outcomes: Certificate of health: Comparison of abstinence or light consumption for 30 days in individuals in the intervention group with a negative screen result versus individuals in the control group. Comparison within the intervention group: Whether individuals with a positive screen result were more likely to cut down on alcohol compared to individuals with a negative screen result at the six-month follow-up. Assessment of crossover: Evaluation of liver disease by transient elastography, ultrasound or CT scan at the hospital not as part of the study among participants randomized as controls. For an assesment of all outcomes, see Supplementary Table 3 Additional File 2. Participant timeline {13} The trial consists of an enrolment visit, allocation to either intervention or usual care and follow-up via a phone interview (see table 4). At the enrolment visit interview, the physician or alcohol therapist from Novavi fills out questionnaires with the participant (Additional file 4). After completing the questionnaires, the patient is allocated to either the intervention or usual care by being handed the sealed envelope with the randomization outcome provided. The intervention will be performed as soon as possible, preferably within two weeks but no later than one month. Usual care (blood samples) will also be performed as soon as possible. Follow-up assessments will be conducted at six months after baseline via interviews by phone. Table 4 Enrolment Allocation Close-out TIMEPOINTS -t 1 Baseline Within 1 month 6 months >2 years ENROLMENT: Eligibility screen X Informed consent X Allocation X INTERVENTIONS: Liver screening with transient elastography and blood tests. X Usual care with offer of blood tests X ASSESSMENTS: Baseline: AUDIT, motivation to cut down, units/week, last alcohol consumption, Phosphatidyl-ethanol, SF-12 v2, PSS, smoking X Follow-up: Alcohol abstinence/light consumption the last 6 months, AUDIT, motivation to cut down, SF-12 v2, PSS, smoking X Abbreviations: AUDIT: Alcohol Use Disorders Identification Test, PSS: Perceived Stress Scale Sample size {14} We plan to include 408 individuals in the study: 272 will be offered the intervention with liver screening based on transient elastography, and 136 will be offered usual care. This number is based on a sample size calculation with the assumption of a favourable alcohol outcome of abstinence or light consumption at follow-up in 66% of the intervention group and 51% of the control group and with a power of 80% and a two-sided significance level of 5%. The expected percentage of 51% with abstinence or light consumption is derived from our pilot study based on 40 participants (36); in addition, it is similar to observations in another study from an alcohol treatment centre (37). We expect loss to follow-up to be negligible because of the three follow-up methods applied. The size of the intervention group will allow a comparison between those who screen positive (FibroScan© indicates liver fibrosis) and those who screen negative. Approximately 20% of patients are expected to have indications of liver fibrosis on FibroScan© (>8 kPa), while 80% are expected to screen negative (data from a pilot trial (36)). A difference in the outcome of abstinence or light consumption of 24% is expected (75% vs. 51% will be light drinkers/abstinent at 6 months) based on a prior study in primary care where a 75% reduction in alcohol consumption after screening positive for liver fibrosis was reported (14). Recruitment {15} The staff at the specialized alcohol treatment centres (Novavi Køge and Novavi Roskilde) will conduct the recruitment and provide both oral and written information. Written information about the study will be displayed in Novavi Køge and Novavi Roskilde for everyone to see and can be sent by email. All individuals attending treatment for alcohol use disorders will be screened for eligibility. Potential participants have the opportunity to contact the researchers for more information about the study, as written in the recruitment material (Additional file 5). The recruiting staff will conduct a screening log for study participation. The enrolment period is planned to be three years but will continue until all 408 patients are included. The last outcome assessment is expected to be performed 3.5 years after the first patient was included. Assignment of interventions: Allocation Sequence generation {16a} Participants are randomized 2:1 to receive the intervention or usual care. The randomization sequence for all 408 participants will be computer generated by the researcher (PD) using the webpage “sealedenvelope.com” before enrolment in the study begins. The randomization sequence for the 408 participants will be made in blocks of 24 so that each treatment site (Novavi Roskilde and Novavi Køge) will have 24 opaque and sealed envelopes delivered at a time. The delivery of 24 envelopes at a time overcomes that the randomization sequence will be made preenrolment and that the number of participants included from each site could not be known beforehand. Concealment mechanism {16b} The block sizes and randomization will be concealed from the staff at the specialized alcohol treatment centres responsible for enrolment. Implementation {16c} The researcher generates the allocation sequence and assembles the randomization envelopes. The alcohol therapist, who enrols participants, will hand the envelope with the randomization outcome to the participant after obtaining informed consent for study participation and after the collection of the baseline variables and, by this approach, assign participants to a randomization group. The therapist will then send an email with the name, study number and phone number of the trial participant to the researcher. Assignment of interventions: Blinding Who will be blinded {17a} The allocation is concealed for the health care professionals at Novavi and the participants until baseline data were collected. Due to the nature of the intervention, neither the participants nor the health care professionals at Novavi could be blinded to the allocation. For the outcome interview, participants will be advised not to disclose the allocation status by the outcome interviewers. No information about the randomization will be revealed in the records at the alcohol treatment centre or the hospital, which will also be evaluated for information about drinking outcomes by the outcome interviewers. It should be noted that while our statistical team cannot be effectively blinded due to the 2:1 allocation, they will not have any involvement with the patients. In addition, health care professionals at Novavi and participants are blinded to the study hypothesis that transient elastography might improve alcohol abstinence or lower alcohol consumption compared to usual care. Procedure for unblinding if needed {17b} The outcome interviewers will remain blinded throughout the study and will not be involved in patient treatment, eliminating the need for unblinding. However, in the event that a participant inadvertently discloses their allocation to the interviewer, the study protocol allows for their continued inclusion. If an envelope containing allocation information is opened prior to collecting baseline data, a new envelope will be provided to ensure the integrity of the blinding procedure. Data collection and management Plans for assessment and collection of outcomes {18a} The participants are assessed at baseline with a range of questionnaires using paper forms, supervised by an alcohol therapist, and at the 6-month follow-up by a project nurse via phone interview (see additional file 4). The 6-month follow-up also includes an alcohol consumption interview with the validated timeline follow-back method and a review of the participant’s electronic medical journal and alcohol treatment journal (38). The baseline assessment takes approximately 30 minutes to complete, and each follow-up assessment takes approximately one hour. To ensure the quality of the data, the assessors are trained in administering each of the different questionnaires. Qualitative Study: Participants’ Experiences The purpose of this qualitative study is to determine how screening for liver disease in individuals receiving alcohol abuse treatment is experienced by those who are invited to participate in screening, the reasons for refusing the screening, and the impact of the screening results on participants’ emotions and health-related behaviour. Data will be collected through semistructured qualitative individual interviews with up to 20 participants (up to 10 from each of the two Novavi locations, as we expect variation in the delivery of the invitation among Novavi’s health professionals) and 5-10 nonparticipants (refusers) in screening for liver disease. The recruitment of interviewed persons will stop when we reach data saturation. The perspectives that may appear in the interviews could be whether the screening offer induces anxiety or concern about being diagnosed with disease, how the screening result affects participants' interest in caring for their own health, and to what extent the result of the screening motivates participants to make lifestyle changes. Interview persons will be recruited in connection with their screening visit at the hospital or, as for refusers, in connection with their screening invitation at Novavi. The data will be organized with NVivo software and will be analysed with a narrative approach (39,40) allowing for the exploration of how the screening invitation, the knowledge of potential liver disease, and the screening result are ascribed meaning and are integrated into the life stories and identities of individuals in alcohol abuse treatment. Qualitative study: Implementation barriers and facilitators The purpose of this qualitative study is to explore the barriers and facilitators among health professionals that may hinder or facilitate the implementation of liver disease screening for individuals receiving alcohol treatment. Ultimately, this research seeks to facilitate the seamless integration of liver fibrosis screening into the fundamental care provided to individuals seeking treatment for alcohol use disorders. Individual semistructured interviews will be conducted with healthcare professionals from Novavi and the Zealand University Hospital. These interviews will be recorded and transcribed, capturing insights before, during, and after the main RCT. The interview questions will be meticulously crafted to comprehensively cover the theoretical domain framework and COM-B model constructs (41–43). The qualitative sample strategy will be guided by the concept of information power and is expected to include 10-15 participants.(44) Follow-up: health economic impact Direct healthcare costs associated with screening and general healthcare costs of the participants, including expenses related to liver scan procedures, follow-up visits, medical consultations, laboratory tests, treatments and prescription medicine, will be analysed throughout the 12 months after the liver scan intervention. Costs will be obtained from diagnosis-related group prices obtained from the National Patient Registry for hospital-based services, reimbursement prices obtained from the National Health Service Registry for primary healthcare services and prescription medicine costs from the National Prescription Registry. Participants' health-related quality of life will be assessed using the validated SF-12 questionnaire at baseline and 6 months after the scan. From the SF-12 questionnaire, data utilities can be derived using a validated conversion algorithm, and quality-adjusted life years (QALYs) will be estimated by multiplying the life years by the utility over the prospective course of 12 months. Indirect societal costs will be estimated from social transfer payments using the DREAM registry (45) A cost-utility analysis will be conducted, analysing the difference in costs divided by the difference in QALYs, comparing the intervention group with the control group at six months. Plans to promote participant retention and complete follow-up {18b} The participants are informed orally and in writing about a six-month follow-up by phone. Participants will be contacted by phone up to 10 times within 2 weeks. We expect loss to follow-up to be negligible because we include information from medical chart reviews as well as reviews of charts from Novavi to assess compliance with alcohol treatment. However, if study participants emigrate, they will be regarded as lost to follow-up. Data management {19} The processing of personal data in the current study will be performed in accordance with the law of data protection, and has received approval from The Danish Data Protection Agency (REG-149-2020). It is the responsibility of the primary investigator to ensure that the handling of personal data will comply with the law of data protection. For the assessment of missing data, see additional file 6. Confidentiality {27} Baseline information and the informed consent will be handled in paper form and completed at Novavi Køge and Novavi Roskilde, where it will be kept in a locked box in a locked room. Afterwards, the baseline information and informed consent will be transferred safely to the medical department, Køge, where the baseline information will be entered into the REDCap (Research Electronic Data Capture) to store the research data safely (46). The remaining documents in paper form–informed consent and baseline information–will always be locked safely in a room where only the researchers have access. The 6-month follow-up phone interview will be conducted in a private room, and the results will be entered directly into REDCap. The trial master file is stored on a local secure online platform with a complete audit trail on all data transactions. Interviews with patients for the qualitative study will be audio-recorded with an encrypted voice recorder. The interviews will be transcribed verbatim, and the interviewees will be given pseudonyms. Audio files and transcripts will be stored on a secure drive. The conversion key will be kept separately in paper form in a locked drawer in a locked room. Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33} No specific biological specimens for genetic or molecular analysis were collected for this study. We verified before the start that all the data needed for the analysis were part of the routine blood samples taken at baseline. Statistical methods Statistical methods for primary and secondary outcomes {20a} Primary outcome The primary outcome (alcohol abstinence or light consumption (≤ 10 units alcohol/week throughout last 30 days) yes/no) will be assessed using logistic regression adjusted for intervention with an invitation to undergo a fibroscan examination and an average number of units per week at inclusion. The primary outcome will be assessed in the intention-to-treat population and, further, in the per-protocol population. In the latter, the inverse probability of treatment weighting will be used to account for the measured confounding factors of age, sex, average number of drinks per week and months in alcohol abuse treatment. Furthermore, we will analyse whether time in treatment for alcohol use disorder is an effect modifier, analysed as an interaction between randomization group and the primary outcome. Secondary outcomes Reduction in the number of heavy drinking days (yes or no) This secondary outcome will be assessed using logistic regression. Reduction in the AUDIT-C score (yes or no, measured on a continuous scale); linear regression Improvement or no decrease in motivation to reduce alcohol consumption (yes or no) or improvement or no decrease in health-related quality of life (yes or no) are calculated as the difference between baseline and follow-up. Linear regression. Staying in alcohol abuse treatment among participants exceeding light drinking levels (yes/no). Logistic regression. improving or not decreasing physical or mental health-related quality of life (Sf-12)). Linear regression. improving or not decreasing smoking Logistic regression. Evaluation of liver disease at the hospital not as part of the study among all participants to assess crossover: whether those randomized as controls had the intervention performed on another occasion (yes/no). Comparison within the intervention group: Patients who screened positive were more likely to reduce their alcohol consumption than those who screened negative. A statistical analysis plan was uploaded to clinical trials before enrolment began (see additional file 6). Interim analyses {21b} There will be no interim analyses. Methods for additional analyses {20b} We will conduct a number of subgroup analyses: compare outcomes between those who screen negative (FibroScan© 8 kPa with those from the control group, and compare outcomes by study site, sex, days in alcohol treatment, and others. Methods in analysis to handling protocol nonadherence and missing data {20c}. If the liver stiffness measurement was not possible due to obesity, etc., patients will be included in the analysis in addition to the controls. Participants who are lost to follow-up due to emigration will also be excluded from this analysis. Follow-up will be possible for all other participants (follow-up procedures are described below). A CONSORT flow chart will present the flow of study participants. Plans to give access to the full protocol, participant-level data and statistical code {31c} The full trial protocol is available from clinicaltrials.gov. The dataset from the current study will be available from the corresponding author upon reasonable request. Oversight and monitoring Composition of the coordinating centre and trial steering committee {5d} The trial steering committee (see title page for members) is composed of a principal investigator, lead investigators, a research physician, a data analyst and statisticians. All authors agreed with the final protocol. Composition of the data monitoring committee and its role and reporting structure {21a} This study does not have a data monitoring committee due to the simplicity and low-risk nature of the study. Regular oversight and monitoring will be carried out by the principal investigators to ensure the study's progress and integrity. Adverse event reporting and harms {22} Transient elastography is a noninvasive test, and the technique is based on ultrasound. Transient elastography is considered safe without adverse events to the patient (26). The emotional impact of further clinical investigations seems to be negligible, at least after four weeks (16) Frequency and plans for auditing trial conduct {23} We intend to perform an audit every eight weeks to review all parts of the research processes, including participant enrolment, consent, eligibility, and allocation to study groups, as well as adherence to trial interventions, reporting of harm, and ensuring the timeliness and accuracy of data collection. Plans for communicating important protocol amendments to relevant parties (e.g., trial participants, ethical committees) {25} The clinical trial registry, sponsors and ethics committee will be notified of any modifications to the trial protocol. Dissemination plans {31a} The trial results will be disseminated to participants, healthcare professionals, the public, and other relevant groups through the publication of peer-reviewed journals and presentations at national and international conferences by the researchers. The results will potentially also be discussed with policymakers to inform political decision-makers about our findings and their potential policy implications. Discussion This study has the potential to offer important insights into the efficacy of transient elastography as a screening approach in individuals motivated to achieve alcohol abstinence. Although screening for liver disease in individuals with harmful alcohol consumption is recommended, it remains unclear whether this screening tool is effective in reducing alcohol intake in this specific population (26). One criterion for implementing a screening program is the availability of an accepted treatment for patients with the recognized disease(47). However, without a simple or fast tool available to effectively reduce alcohol intake, the question of whether we have sufficient treatment arises, making this study particularly important. This study aims to investigate whether a screening modality such as FibroScan© can reduce alcohol intake compared to that of patients who do not undergo screening. Observational data suggest that disease screening may serve as a catalyst for behavioural change, which has been observed for tobacco cessation in the setting of lung cancer screening (48) However, no studies have been conducted to investigate this for alcohol and FibroScan© in patients with alcohol use disorder. Therefore, this trial represents the first RCT to examine the effects of FibroScan© screening on alcohol consumption in patients diagnosed with AUD. Limitations: One potential limitation of the study is the measurement of the primary endpoint, which is alcohol abstinence or light consumption. This registration relies on self-reporting and is retrospective, potentially introducing limitations in reliability. However, this limitation was mitigated by using the timeline follow-back (TLFB) method, which has been extensively tested and evaluated (38). Importantly, as described above, steps will be taken to blind outcome assessors who perform the interviews. To further enhance the accuracy and validity of the data, the information provided will be supplemented and verified with medical and alcohol centre records. This approach ensures a comprehensive assessment of alcohol consumption and reduces the potential influence of social factors and respondent characteristics (such as patients with alcohol dependence tending to portray themselves more negatively in terms of heavy drinking days). If we were to utilize an alcohol marker such as phosphatidyl ethanol for follow-up assessments, we would encounter limitations due to the potential loss to follow-up, primarily consisting of patients who have experienced alcohol relapse, as observed in our pilot project. In this project, it was noted that the individuals we were unable to reach for follow-up indeed experienced relapse, as indicated by their health records. Another limitation is that the control group receives an intervention that is slightly more active than usual practice, i.e., participants in the control group will be invited to a blood test, whereas in normal circumstances, people need to contact their general practitioner on their own initiative), potentially leading to contamination and blurring the difference between the intervention and control groups. Blood tests are offered to the control group to prevent them from seeking their general practitioner and having blood tests and potentially transient elastography performed elsewhere, which could introduce crossover bias (49). It should be noted that if the intervention group demonstrates better outcomes, it would be challenging to attribute the results solely to the scanning intervention. This is because the intervention involves a combination of a hospital visit, medical consultation, motivational conversation, and other factors. Therefore, it becomes difficult to isolate the specific contribution of the transient elastography procedure itself in influencing the outcomes. Strengths: Some strengths of this study are the randomized controlled trial design with allocation concealment and the use of three methods for collecting follow-up information, which will minimize loss to follow-up. Additionally, the primary endpoint and follow-up duration, as the choice of using abstinence or light consumption over the last 30 days as the primary endpoint, assessed 6 months after randomization, provide a clinically relevant and meaningful measure of behaviour change. The use of transient elastography (FibroScan©) as a noninvasive screening tool for liver fibrosis is a significant strength of the study. This approach offers a convenient and relatively low-risk method for detecting liver disease in its early stages compared to the invasive procedure of liver biopsy, potentially enabling early intervention and improved patient outcomes. Emphasis on Alcohol Use Disorder Treatment: By focusing on individuals receiving treatment for alcohol use disorder, the study design targets a population that is more likely to be motivated for alcohol abstinence. This emphasis increases the relevance and potential impact of the findings on clinical practice and patient care in the context of alcohol-related liver disease. Perspectives: This study has significant implications for the field of alcohol dependence and screening for chronic liver disease. It addresses the crucial question of whether screening for chronic liver disease contributes to better outcomes for individuals with alcohol use disorders. Trial status Study protocol version number and date: 02. Version 05.01.2023 Recruitment began: May 2023 Recrutiment is expected to be completed: November 2026. Abbreviations SPIRIT Standard Protocol Items:Recommendations for Clinical Interventional Studies ALD alcohol-related liver disease FIB-4 Fibrosis index based on four factors IQR interquartile range kPa kilopascal AUDIT C Alcohol Use Disorder Identification Test SF-12 v2 Short-form 12-item scale, version 2 PSS Perceived Stress Scale CT computed tomography COM-B model capability, opportunity, motivation and behaviour model REDCap Research Electronic Data Capture TLFB Timeline Follow-Back SAP Statistical Analysis Plan Declarations Acknowledgements Not applicable Authors’ contributions {31b} PD: Research physician: wrote the draft of the final trial report and contributed to the study design. GA: Principal investigator; PJ: Lead investigator: conceived the study idea, developed the study design, led the proposal and protocol development and reviewed the manuscript. LGM contributed to the study design, development of the protocol, review of the manuscript and was responsible for the hospital study facilities. SD contributed to the study design and review of the manuscript. KB contributed to the study design and review of the manuscript. LM contributed to the study design and review of the manuscript. MWJ, a lead trial data analyst, developed the statistical analysis plan and reviewed the manuscript. JCG, a qualitative researcher, contributed to the qualitative study design and review of the manuscript. KJJ was responsible for the health economic impact study. All the authors have read and approved the final manuscript. Funding {4} We, the researchers, have initiated the research project, no companies or institutions have initiated the project, and there are no financial or marketing interests associated with the project. Gro Askgaard, Zealand University Hospital, received funding from Den fællesregionale pulje til forskning i forebyggelse (1.198.000 DKK), Fonden Novavi (900.000 DKK) and the Novo Nordisk Foundation (2.998.000 DKK). This funding will cover salaries for researchers, project nurses, and administrators and will pay for analyses of blood samples. The funders had no role in the research design or decision to publish. Moreover, the researchers in this project have no commitments to the funders. Availability of data and materials {29} MWJ and JP will have access to the raw dataset. Following the analysis of the primary and secondary outcomes, PD, GA, LGM, and PJ will also be provided access to the dataset. Ethics approval and consent to participate {24} The study protocol was approved by The Committee on Health Research Ethics of Region Zealand, Denmark (Project ID: SJ-995, EMN-2022-05916). The protocol is available at clinicaltrials.gov. All patients provided written informed consent and were not offered financial compensation. The study was conducted under the Helsinki Declaration. Consent for publication {32} The results will be published regardless of whether they are positive, negative, or inconclusive via www.clinicaltrials.gov Competing interests {28} The authors declare that they have no competing interests. References Chan AW, Tetzlaff JM, Altman DG, Laupacis A, Gøtzsche PC, Krleža-Jerić K et al. SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med [Internet]. 2013 Feb 5 [cited 2024 Jun 10];158(3):200–7. https://pubmed.ncbi.nlm.nih.gov/23295957/ . Asrani SK, Mellinger J, Arab JP, Shah VH. Reducing the Global Burden of Alcohol-Associated Liver Disease: A Blueprint for Action. Hepatology [Internet]. 2021 May 1 [cited 2024 Jun 10];73(5):2039–50. https://pubmed.ncbi.nlm.nih.gov/32986883/ . Rehm J, Shield KD. Global Burden of Alcohol Use Disorders and Alcohol Liver Disease. 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Int J Epidemiol [Internet]. 2015 Dec 1 [cited 2024 Jun 10];44(6):2006–19. https://pubmed.ncbi.nlm.nih.gov/26377509/ . Additional File 4 Additional File 4 is not available with this version. Supplementary Files Additionalfile1consentform.docx Additionalfile2Tables.docx Additionalfile3Manualforinterview.docx Additionalfile5RecruitmentMaterial.docx Additionalfile6StatisticalAnalysisPlan.docx Cite Share Download PDF Status: Published Journal Publication published 28 Oct, 2025 Read the published version in Trials → Version 1 posted Editorial decision: Minor revision 09 May, 2025 Reviewers agreed at journal 03 Aug, 2024 Reviewers invited by journal 01 Aug, 2024 Editor assigned by journal 09 Jul, 2024 First submitted to journal 19 Jun, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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information","content":"\u003cp\u003eThis protocol was written in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Studies (SPIRIT) guidelines\u0026nbsp;(1)\u003c/p\u003e\n\u003cp\u003eNote: The numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/).\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"639\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.11580594679186%\" valign=\"top\"\u003e\n \u003cp\u003eTitle {1}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.88419405320813%\" valign=\"top\"\u003e\n \u003cp\u003eThe Liver Care Trial: Screening for liver fibrosis in individuals attending treatment for alcohol use disorder - study protocol for a randomized controlled study\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.11580594679186%\" valign=\"top\"\u003e\n \u003cp\u003eTrial registration {2a and 2b}.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.88419405320813%\" valign=\"top\"\u003e\n \u003cp\u003eClinicalTrials.gov. Unique Protocol identifier: NCT05855031. Date of registration: 20-04-2023\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.11580594679186%\" valign=\"top\"\u003e\n \u003cp\u003eProtocol version {3}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.88419405320813%\" valign=\"top\"\u003e\n \u003cp\u003eVersion 2.0 - 05.01.2023\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.11580594679186%\" valign=\"top\"\u003e\n \u003cp\u003eFunding {4}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.88419405320813%\" valign=\"top\"\u003e\n \u003cp\u003eThis trial is funded by\u0026nbsp;The cross-regional pool for research in prevention ID: R201-A4451 and the Novo Nordisk Foundation ID: NF22OC0079565.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.11580594679186%\" valign=\"top\"\u003e\n \u003cp\u003eAuthor details {5a}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.88419405320813%\" valign=\"top\"\u003e\n \u003cp\u003e\u003csup\u003ea\u003c/sup\u003eMedical Department, Section of Gastroenterology and Hepatology, Zealand University Hospital, K\u0026oslash;ge, Denmark\u003c/p\u003e\n \u003cp\u003e\u003csup\u003eb\u003c/sup\u003eDepartment of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark\u003c/p\u003e\n \u003cp\u003e\u003csup\u003ec\u003c/sup\u003eCenter for Clinical Research and Prevention, Frederiksberg University Hospital, Copenhagen, Denmark\u003c/p\u003e\n \u003cp\u003e\u003csup\u003ed\u003c/sup\u003eNovavi Alcohol treatment centre K\u0026oslash;ge, K\u0026oslash;ge, Denmark\u003c/p\u003e\n \u003cp\u003e\u003csup\u003ee\u003c/sup\u003eInstitute for Clinical Medicine, University of Copenhagen\u003c/p\u003e\n \u003cp\u003e\u003csup\u003ef\u003c/sup\u003ePalliative Care Unit, Copenhagen University Hospital \u0026ndash; Hvidovre, Denmark\u003c/p\u003e\n \u003cp\u003e\u003csup\u003eg\u003c/sup\u003eSection of Biostatistics, Department of Public Health, University of Copenhagen\u003c/p\u003e\n \u003cp\u003e\u003csup\u003eh\u003c/sup\u003eDepartment of Clinical Research, Hvidovre University Hospital, \u0026nbsp;Hvidovre, Denmark\u003c/p\u003e\n \u003cp\u003e\u003csup\u003eI\u003c/sup\u003eDepartment of Health and Social Context, National Institute of Public Health, University of Southern Denmark, Denmark\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.11580594679186%\" valign=\"top\"\u003e\n \u003cp\u003eName and contact information for the trial sponsor {5b}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.88419405320813%\" valign=\"top\"\u003e\n \u003cp\u003eDanish Regions: Dampf\u0026aelig;rgevej 22, 2100\u0026nbsp;K\u0026oslash;benhavn \u0026Oslash; (DK). Phone number +45 3529 8100\u003c/p\u003e\n \u003cp\u003eThe Novavi Foundation: Peter Bangs Vej 7A, Bygning 9 2. etage, 2000 Frederiksberg (DK). Phone number\u0026nbsp;\u003ca href=\"tel:+45%2039%2045%2054%2055\"\u003e+45 3945 5455\u003c/a\u003e\u003c/p\u003e\n \u003cp\u003eThe Novo Nordisk Foundation: Tuborg Havnevej 19, 2900 Hellerup (DK).\u0026nbsp;Phone number\u0026nbsp;\u003ca href=\"tel:+%2045%2035%2027%2066%2000\"\u003e+ 45 3527 6600\u003c/a\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.11580594679186%\" valign=\"top\"\u003e\n \u003cp\u003eRole of sponsor {5c}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.88419405320813%\" valign=\"top\"\u003e\n \u003cp\u003eThe funders have no role in research design, data\u0026nbsp;collection, management, analysis, and interpretation of data; writing of the article or decision to publish. Moreover, the researchers in this project have no commitments to the funders.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Introduction","content":"\n\u003ch3\u003eBackground and rationale {6a}\u003c/h3\u003e\n\u003cp\u003eAlcohol-related liver disease (ALD) represents a significant global health challenge, contributing to an annual death toll of 500,000 individuals worldwide (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). This high number highlights the urgent need for effective prevention strategies to combat the consequences of ALD.\u003c/p\u003e \u003cp\u003eCurrently, the prognosis for individuals diagnosed with ALD remains poor, with a mortality risk of approximately 35% within the first year following diagnosis (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). This high mortality risk is likely caused by the late-stage detection of ALD, as ALD is often diagnosed when complications of liver failure have developed (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). For example, in Denmark, approximately 50% of patients have already developed cirrhosis with complications at the time of their ALD diagnosis (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSurvival in patients with ALD could potentially improve if ALD was detected before liver-related complications developed, and importantly, if this earlier detection of ALD led to a reduction in alcohol consumption and preferably complete abstinence (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Fortunately, advances in technology have paved the way for earlier detection of ALD by screening with a simple and noninvasive technique known as transient elastography (FibroScan\u0026copy;) (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Transient elastography can detect ALD before symptoms of liver disease appear.\u003c/p\u003e \u003cp\u003eIt remains uncertain whether screening for ALD before the emergence of health problems is sufficient to induce a reduction in alcohol consumption and improve the prognosis in individuals with high alcohol consumption. To date, there are no randomized controlled trials (RCTs) comparing transient elastography with usual care to evaluate the efficacy abstinence or light-controlled consumption (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Individuals receiving alcohol treatment are a suitable study population to offer a screening for liver fibrosis since they are likely to be motivated to abstain from alcohol use, and due to their 10 years of abusive alcohol intake, they constitute a high-risk group for ALD according to the European Association of the Study of Liver Disease (EASL) (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eObservational studies have indicated that appropriate behavioural advice in the context of health problems motivates a reduction in alcohol consumption (\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). However, whether screening for liver fibrosis leads to a better prognosis than usual care cannot be established by observational evidence; for this, we need an RCT (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThere is also concern regarding the potential negative consequences of receiving a normal screening result, a phenomenon termed the \"certificate-of-health effect\" (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). The \"certificate-of-health effect\" has been observed in a colorectal cancer screening study, where individuals with normal screening findings had more weight gain than did the control group at follow-up three years later (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). In individuals with alcohol use disorders, one could fear that a normal screening result indicating a healthy liver may inadvertently drive steady or even increased alcohol consumption.\u003c/p\u003e \u003cp\u003ePsychologically, the offer of screening for ALD could cause anxiety about having or being at risk of a chronic life-threatening disease (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). False-negative results of liver stiffness measurements are very rare, and the false positive rate is approximately 7% (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e); thus, some patients are wrongly mistaken for having chronic liver disease. On the other hand, screening for liver disease in individuals attending alcohol misuse treatment may lead to an experience of interest from the healthcare system rather than neglect (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Hence, there is a need to explore the psychological effects of screening for ALD. Furthermore, the transition of clinical innovations into routine practice is often a slow process, often taking years for widespread adoption (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Therefore, there is a need to understand the barriers to effectively integrating screening procedures into standard care if we are to improve outcomes for individuals seeking treatment for alcohol use disorders.\u003c/p\u003e\n\u003ch3\u003eObjectives {7}\u003c/h3\u003e\n\u003cp\u003eThe primary objective of this study is to evaluate whether screening for liver fibrosis with transient elastography leads to a reduction in alcohol intake in individuals attending alcohol treatment with no prior history of liver disease. The primary outcome is \u0026ldquo;abstinence or light consumption\u0026rdquo; (\u0026le;\u0026thinsp;10 units a week) 6 months after randomization.\u003c/p\u003e \u003cp\u003eWe will test the hypothesis that screening for liver fibrosis with transient elastography in individuals attending treatment for alcohol use disorders will increase the proportion of individuals who are abstinent or with light-controlled consumption by 15% percent points or more after six months of follow-up compared to usual care. We find that such a difference represents a clinically significant difference to highlight the effectiveness of the screening.\u003c/p\u003e \u003cp\u003eQualitative objectives\u003c/p\u003e \u003cp\u003eWe will investigate the experiences of participants in liver screening regarding its impact on their emotions and behavior and the reasons for nonparticipation for those who refuse to participate in the screening. Furthermore, we aim to elucidate the barriers and facilitators that health professionals face when implementing liver screening in clinical practice for individuals receiving treatment for alcohol use disorders.\u003c/p\u003e \u003cp\u003eHealth-economic impact\u003c/p\u003e \u003cp\u003eWe plan longer-term follow-up after 2\u0026ndash;3 years to investigate the health-economic impact of screening for liver disease by transient elastography versus usual care on healthcare costs, quality-adjusted life years and employment. The data for these analyses will come from Danish nationwide registries.\u003c/p\u003e\n\u003ch3\u003eTrial design {8}\u003c/h3\u003e\n\u003cp\u003eThe study is a multicentre, open-label, randomized, controlled trial of transient elastography screening versus usual care with a 2:1 allocation ratio and blinded evaluation of the primary outcome of abstinence or light consumption (\u0026le;\u0026thinsp;10 units a week) in the last 30 days at the six-month follow-up.\u003c/p\u003e \u003cp\u003eIn addition, as mentioned above, two qualitative studies and one long-term follow-up study are planned. These are only described in section 18a.\u003c/p\u003e"},{"header":"Methods: Participants, interventions and outcomes","content":"\u003cp\u003e\u003cstrong\u003eStudy setting and usual care {9}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants are recruited from two specialized alcohol outpatient treatment centres, Novavi K\u0026oslash;ge and Novavi Roskilde, in Denmark. Together, these centres serve approximately 350 individuals annually who are seeking treatment for alcohol use disorder. Novavi is a not-for-profit organization that runs open outpatient treatment facilities in the greater capital area of Denmark and has previously participated in several research studies\u0026nbsp;(22,23). Novavi offers psychosocial treatment based on motivational interviewing and cognitive behavioural therapy, and if needed, in combination with pharmacological treatment for alcohol use disorder, in line with guideline recommendations\u0026nbsp;(24). All Danish citizens have access to universal, tax-financed healthcare, including outpatient treatment for alcohol use disorder, so there is no out-of-pocket payment for those who seek treatment in Novavi\u0026rsquo;s facilities\u0026nbsp;(25). Individuals seeking treatment for alcohol use disorder can be referred by general practitioners, hospital doctors or, most commonly, they can refer themselves.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe intervention will be performed at the Department of Gastroenterology and Hepatology, Medical Department, Zealand University Hospital.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEligibility criteria {10}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants must provide written, informed consent before any study procedures occur (Additional file 1).\u0026nbsp;Participants are\u0026nbsp;eligible for study participation if they attend community-based outpatient treatment for alcohol use disorder\u0026nbsp;(International Classification of Disease,\u0026nbsp;version 10: F10.2: alcohol dependence or F10.1: harmful alcohol use)\u0026nbsp;at Novavi K\u0026oslash;ge or Novavi Roskilde and are \u0026gt; 18 years of age.\u003c/p\u003e\n\u003cp\u003eThe exclusion\u0026nbsp;criteria are severe liver disease known by the participant or inability to speak Danish.\u003c/p\u003e\n\u003cp\u003eHealth Professionals performing the intervention are eligible if they had completed a 1-day course in motivational interviewing and had completed at least 20 supervised transient elastographies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWho will take informed consent? {26a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePhysicians and alcohol therapists employed at Novavi alcohol treatment centre will inform eligible participants about the study orally and in writing. Participants sign an informed consent for study participation after the necessary reflection time.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdditional consent provisions for collection and use of participant data and\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003ebiological specimens {26b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003en/a \u0026ndash; No biological\u0026nbsp;specimens\u0026nbsp;will be collected.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterventions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExplanation for the choice of comparators {6b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe comparison group, consisting of participants randomized as controls, will receive usual care provided at the alcohol treatment centre and\u0026nbsp;will receive\u0026nbsp;routine blood samples, including FIB-4\u0026nbsp;See Supplementary Table 1, Additional file 2\u0026nbsp;(26,27). The FIB-4 is a fibrosis index based on four factors and is a is a screening tool used for the initial screening of liver fibrosis\u0026nbsp;(28).\u003c/p\u003e\n\u003cp\u003eAccording to\u0026nbsp;the\u0026nbsp;EASL, blood testing with FIB-4 measurement is considered the current standard practice(26).\u0026nbsp;However, we suspect that the use of FIB-4 is not widely implemented in current clinical practice. Therefore, the control group in this study will receive a more comprehensive offer\u0026nbsp;than\u0026nbsp;individuals undergoing alcohol treatment who typically do not have access to FIB-4 testing.\u003c/p\u003e\n\u003cp\u003eParticipants randomized as controls are offered the possibility of blood samples being collected on the patients\u0026rsquo; own accord. Participants will be informed by a physician after blood sampling only if the blood samples indicate abnormalities.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIntervention description {11a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe intervention consists of 1) transient elastography using FibroScan\u0026copy;, 2) clinical examination of weight, height and waist circumference, 3) routine blood sampling see Supplementary Table 1 Additional file 2, and 4) the results of the transient elastography delivered in the spirit of motivational interviewing, including a leaflet with description of alcohol-related diseases and the health-related benefits of cutting down (29).\u003c/p\u003e\n\u003cp\u003eLiver stiffness will be measured using FibroScan\u0026copy;. FibroScan\u0026copy; (transient elastography) works by measuring shear wave velocity with an ultrasound probe. FibroScan\u0026copy; is used to assess liver stiffness, which is correlated with liver fibrosis. FibroScan\u0026copy; is safe, does not cause adverse events and is used in daily clinical practice. Liver fibrosis will be defined as a test result \u0026gt; 8.0 kPa with 10 successful measurements and an interquartile range (IQR) \u0026lt; 30% of the median\u0026nbsp;(8). Participants will receive an explanation of the procedure and be required to fast for four hours before the appointment. If liver stiffness measured by the FibroScan\u0026copy; was not possible due to obesity, etc., the FIB-4 score will be used instead.\u003c/p\u003e\n\u003cp\u003eThe participant undergoing transient elastography will have the exact test result of the FibroScan\u0026copy; explained promptly by the healthcare professional performing the FibroScan\u0026copy; and whether this indicates liver fibrosis or not. Moreover, the results will be written on the leaflet about alcohol-related diseases. If the blood sample results are abnormal, a physician will contact the participant by phone.\u003c/p\u003e\n\u003cp\u003eThe intervention will be delivered by a healthcare professional trained in motivational interviewing with a semistructured manual developed by a certified motivational interviewing coach (Additional File 3). If the FibroScan\u0026copy; is \u0026lt;8 kPa, the response is \u0026ldquo;The liver is still soft\u0026rdquo;, whereas for those with a FibroScan\u0026copy; \u0026ge; 8 kPa, it will be \u0026ldquo;This may be a sign that the liver has become firmer because it has been working over time and further investigations are necessary to find this out\u0026rdquo;.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCriteria for discontinuing or modifying allocated interventions {11b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients may withdraw consent to participate in the trial at any time without any justification.\u003c/p\u003e\n\u003cp\u003eIf the FibroScan\u0026copy;\u0026nbsp;or the FIB-4 index suggests liver fibrosis (FibroScan\u0026copy;\u0026nbsp;\u0026gt; 8.0 kPa or FIB-4\u0026nbsp;\u0026sup3;\u0026nbsp;1.30) or the blood samples reveal anaemia or vitamin deficiencies, the participant will be offered routine assessment for this at the hospital department where the study takes place.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStrategies to improve adherence to interventions {11c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eResearchers will contact participants by phone within days of enrolment to schedule a transient elastography appointment within four weeks (preferably 2). Up to 10 calls will be made within two weeks after enrolment, if needed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRelevant concomitant care permitted or prohibited during the trial {11d}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe participants in the study are permitted to participate in other interventions during the time of the trial, such as examinations for liver disease. If a participant has an examination during the trial, it will be detected in the participant\u0026rsquo;s electronic medical record at the follow-up, and the type of examination will be reported. No concomitant care is prohibited during the trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProvisions for post-trial care {30}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients will receive continued care according to the standard procedures of Novavi centres during and after the end of the study. If the participants have been referred to the hospital department, the diagnostic investigation will proceed after the trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcomes {12}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePrimary outcome:\u003c/p\u003e\n\u003cp\u003eAlcohol abstinence or light consumption (\u0026le; 10 units/week) throughout the last 30 days (yes/no) was assessed at the six-month follow-up, for evaluation of primary outcome see Supplementary Table 2 Additional File 2. Ten units of alcohol/week is the \u0026ldquo;sensible drinking limit\u0026rdquo; in Denmark\u0026nbsp;(30),\u0026nbsp;and alcohol consumption below this limit minimizes the risk of ALD\u0026nbsp;(8).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe secondary outcomes are heavy drinking days, perceived alcohol problems (AUDIT C score), motivation to reduce alcohol consumption, health-related quality of life (SF-12 v2) and stress management (PSS)\u0026nbsp;(31\u0026ndash;33)\u0026nbsp;(Additional file 4).\u003c/p\u003e\n\u003cp\u003eHeavy drinking increases the risk of ALD independently of average alcohol intake (34); a heavy drinking day is defined for men as consuming five or more drinks and for women as consuming 4 or more drinks (35)\u003c/p\u003e\n\u003cp\u003eOther secondary outcomes:\u003c/p\u003e\n\u003cp\u003eCertificate of health:\u0026nbsp;Comparison of\u0026nbsp;abstinence or light consumption\u0026nbsp;for\u0026nbsp;30 days in individuals in the intervention group with a negative\u0026nbsp;screen\u0026nbsp;result versus individuals in the control group.\u003c/p\u003e\n\u003cp\u003eComparison within the intervention group: Whether individuals with a positive\u0026nbsp;screen\u0026nbsp;result were more likely to cut down on alcohol compared to individuals with a negative\u0026nbsp;screen\u0026nbsp;result at\u0026nbsp;the\u0026nbsp;six-month\u0026nbsp;follow-up.\u003c/p\u003e\n\u003cp\u003eAssessment of\u0026nbsp;crossover: Evaluation of liver disease by transient elastography, ultrasound or CT scan at the hospital not as part of the study among participants randomized as controls.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFor an assesment of all outcomes, see Supplementary Table 3 Additional File 2.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eParticipant timeline {13}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe trial consists of an enrolment visit, allocation to either intervention or usual care and follow-up via a phone interview (see table 4). At the enrolment visit interview, the physician or alcohol therapist from Novavi fills out questionnaires with the participant (Additional file 4). After completing the questionnaires, the patient is allocated to either the intervention or usual care by being handed the sealed envelope with the randomization outcome provided. The intervention will be performed as soon as possible, preferably within two weeks but no later than one month. Usual care (blood samples) will also be performed as soon as possible. Follow-up assessments will be conducted at six months after baseline via interviews by phone.\u003c/p\u003e\n\u003cp\u003eTable 4\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"614\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.24755700325733%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.472312703583063%\"\u003e\n \u003cp\u003e\u003cstrong\u003eEnrolment\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAllocation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.127035830618894%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eClose-out\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.843648208469055%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.24755700325733%\"\u003e\n \u003cp\u003e\u003cstrong\u003eTIMEPOINTS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.472312703583063%\"\u003e\n \u003cp\u003e\u003cem\u003e-t\u003csub\u003e1\u003c/sub\u003e\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003eBaseline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.749185667752442%\"\u003e\n \u003cp\u003e\u003cem\u003eWithin 1 month\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e\u003cem\u003e6 months\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.843648208469055%\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026gt;2 years\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.24755700325733%\"\u003e\n \u003cp\u003e\u003cstrong\u003eENROLMENT:\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.472312703583063%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.749185667752442%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.843648208469055%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.24755700325733%\"\u003e\n \u003cp\u003eEligibility screen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.472312703583063%\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.749185667752442%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.843648208469055%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.24755700325733%\"\u003e\n \u003cp\u003eInformed consent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.472312703583063%\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.749185667752442%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.843648208469055%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.24755700325733%\"\u003e\n \u003cp\u003eAllocation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.472312703583063%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.749185667752442%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.843648208469055%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.24755700325733%\"\u003e\n \u003cp\u003e\u003cstrong\u003eINTERVENTIONS:\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.472312703583063%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.749185667752442%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.843648208469055%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.24755700325733%\"\u003e\n \u003cp\u003e\u003cem\u003eLiver screening with transient elastography and blood tests.\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.472312703583063%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.749185667752442%\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.843648208469055%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.24755700325733%\"\u003e\n \u003cp\u003e\u003cem\u003eUsual care with offer of blood tests\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.472312703583063%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.749185667752442%\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.843648208469055%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.24755700325733%\"\u003e\n \u003cp\u003e\u003cstrong\u003eASSESSMENTS:\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.472312703583063%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.749185667752442%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.843648208469055%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.24755700325733%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eBaseline:\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e\u0026nbsp;AUDIT, motivation to cut down, units/week, last alcohol consumption, Phosphatidyl-ethanol, SF-12 v2, PSS, smoking\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.472312703583063%\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.749185667752442%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.843648208469055%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.24755700325733%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eFollow-up:\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e\u0026nbsp;Alcohol abstinence/light consumption the last 6 months, AUDIT, motivation to cut down, SF-12 v2, PSS, smoking\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.472312703583063%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.749185667752442%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.843648208469055%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: AUDIT:\u0026nbsp;Alcohol Use Disorders Identification Test, PSS:\u0026nbsp;Perceived Stress Scale\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample size {14}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe plan to include 408 individuals in the study: 272 will be offered the intervention with liver screening based on transient elastography, and 136 will be offered usual care. This number is based on a sample size calculation with the assumption of a favourable alcohol outcome of abstinence or light consumption at follow-up in 66% of the intervention group and 51% of the control group and with a power of 80% and a two-sided significance level of 5%. The expected percentage of 51% with abstinence or light consumption is derived from our pilot study based on 40 participants (36); in addition, it is similar to observations in another study from an alcohol treatment centre (37). We expect loss to follow-up to be negligible because of the three follow-up methods applied. The size of the intervention group will allow a comparison between those who screen positive (FibroScan\u0026copy; indicates liver fibrosis) and those who screen negative. Approximately 20% of patients are expected to have indications of liver fibrosis on FibroScan\u0026copy; (\u0026gt;8 kPa), while 80% are expected to screen negative (data from a pilot trial (36)). A difference in the outcome of abstinence or light consumption of 24% is expected (75% vs. 51% will be light drinkers/abstinent at 6 months) based on a prior study in primary care where a 75% reduction in alcohol consumption after screening positive for liver fibrosis was reported (14).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRecruitment {15}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe staff at the specialized alcohol treatment centres (Novavi K\u0026oslash;ge and Novavi Roskilde) will conduct the recruitment and provide both oral and written information. Written information about the study will be displayed in Novavi K\u0026oslash;ge and Novavi Roskilde for everyone to see and can be sent by email. All individuals attending treatment for alcohol use disorders will be screened for eligibility. Potential participants have the opportunity to contact the researchers for more information about the study, as written in the recruitment material (Additional file 5). The recruiting staff will conduct a screening log for study participation. The enrolment period is planned to be three years but will continue until all 408 patients are included. The last outcome assessment is expected to be\u0026nbsp;performed\u0026nbsp;3.5 years after the first patient was included.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssignment of interventions: Allocation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSequence generation {16a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants are randomized 2:1 to receive the intervention or usual care.\u003c/p\u003e\n\u003cp\u003eThe randomization sequence for all 408 participants will be computer generated by the researcher (PD) using the webpage \u0026ldquo;sealedenvelope.com\u0026rdquo; before enrolment in the study begins.\u003c/p\u003e\n\u003cp\u003eThe randomization sequence for the 408 participants will be made in blocks of 24 so that each treatment site (Novavi Roskilde and Novavi K\u0026oslash;ge) will have 24 opaque and sealed envelopes delivered at a time. The delivery of 24 envelopes at a time overcomes that the randomization sequence will be made preenrolment and that the number of participants included from each site could not be known beforehand.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConcealment mechanism {16b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe block sizes and randomization will be concealed from the staff at the specialized alcohol treatment centres responsible for enrolment.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImplementation {16c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe researcher generates the allocation sequence and assembles the randomization envelopes. The alcohol therapist, who enrols participants, will hand the envelope with the randomization outcome to the participant after obtaining informed consent for study participation and after the collection of the baseline variables and, by this approach, assign participants to a randomization group.\u003c/p\u003e\n\u003cp\u003eThe therapist will then send an email with the name, study number and phone number of the trial participant to the researcher.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssignment of interventions: Blinding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWho will be blinded {17a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe allocation is concealed for the\u0026nbsp;health care professionals at Novavi\u0026nbsp;and the\u0026nbsp;participants\u0026nbsp;until baseline data\u0026nbsp;were\u0026nbsp;collected.\u003c/p\u003e\n\u003cp\u003eDue to the nature of the intervention, neither\u0026nbsp;the\u0026nbsp;participants nor\u0026nbsp;the health care professionals at Novavi\u0026nbsp;could\u0026nbsp;be blinded to the allocation. For the outcome interview, participants will be advised not to disclose the allocation status by the outcome interviewers. No information about the randomization will be revealed in the records at\u0026nbsp;the\u0026nbsp;alcohol treatment centre or the hospital,\u0026nbsp;which will also be evaluated for information about drinking outcomes by the outcome interviewers. It should be noted that while our statistical team cannot be effectively blinded due to the 2:1 allocation, they will not have any involvement with the patients. In addition,\u0026nbsp;health care professionals at Novavi and\u0026nbsp;participants are blinded to the study hypothesis that transient elastography might improve alcohol abstinence or lower\u0026nbsp;alcohol\u0026nbsp;consumption compared to usual care.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;Procedure for unblinding if needed {17b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe outcome interviewers will remain blinded throughout the study and will not be involved in patient treatment, eliminating the need for unblinding. However, in the event that a participant inadvertently discloses their allocation to the interviewer, the study protocol allows for their continued inclusion. If an envelope containing allocation information is opened prior to collecting baseline data, a new envelope will be provided to ensure the integrity of the blinding procedure.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData collection and management\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans for assessment and collection of outcomes {18a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe participants are assessed at baseline with a range of questionnaires using paper forms, supervised by an alcohol therapist,\u0026nbsp;and at\u0026nbsp;the\u0026nbsp;6-month follow-up by a project nurse via phone interview\u0026nbsp;(see additional file 4). The 6-month follow-up also includes an alcohol consumption interview with the validated timeline follow-back method and a review of the participant\u0026rsquo;s electronic medical journal and alcohol treatment journal\u0026nbsp;(38).\u003c/p\u003e\n\u003cp\u003eThe baseline assessment takes approximately 30 minutes to complete, and each follow-up assessment takes approximately one\u0026nbsp;hour. To ensure the quality of the data, the assessors are trained in administering each of the different questionnaires.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eQualitative Study: Participants\u0026rsquo; Experiences\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe purpose of this qualitative study is to determine how screening for liver disease in individuals receiving alcohol abuse treatment is experienced by those who are invited to participate in screening, the reasons for refusing the screening, and the impact of the screening results on participants\u0026rsquo; emotions and health-related behaviour. Data will be collected through semistructured qualitative individual interviews with up to 20 participants (up to 10 from each of the two Novavi locations, as we expect variation in the delivery of the invitation among Novavi\u0026rsquo;s health professionals) and 5-10 nonparticipants (refusers) in screening for liver disease. The recruitment of interviewed persons will stop when we reach data saturation. The perspectives that may appear in the interviews could be whether the screening offer induces anxiety or concern about being diagnosed with disease, how the screening result affects participants\u0026apos; interest in caring for their own health, and to what extent the result of the screening motivates participants to make lifestyle changes. Interview persons will be recruited in connection with their screening visit at the hospital or, as for refusers, in connection with their screening invitation at Novavi. The data will be organized with NVivo software and will be analysed with a narrative approach\u0026nbsp;(39,40)\u0026nbsp;allowing for the exploration of how the screening invitation, the knowledge of potential liver disease, and the screening result are ascribed meaning and are integrated into the life stories and identities of individuals in alcohol abuse treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eQualitative study: Implementation barriers and facilitators\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe purpose of this qualitative study is to explore the barriers and facilitators among health professionals that may hinder or facilitate the implementation of liver disease screening for individuals\u0026nbsp;receiving\u0026nbsp;alcohol treatment. Ultimately, this research seeks to facilitate the seamless integration of liver fibrosis screening into the fundamental care provided to individuals seeking treatment for alcohol use disorders. Individual semistructured interviews will be conducted with healthcare professionals from Novavi and the Zealand University Hospital. These interviews will be recorded and transcribed, capturing insights before, during, and after the main RCT. The interview questions will be meticulously crafted to comprehensively cover the theoretical domain framework and COM-B model constructs\u0026nbsp;(41\u0026ndash;43). The qualitative sample strategy will be guided by the concept of information power and is expected to include 10-15 participants.(44)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFollow-up: health economic impact\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDirect healthcare costs associated with screening and general healthcare costs of the participants, including expenses related to liver scan procedures, follow-up visits, medical consultations, laboratory tests, treatments and prescription medicine, will be analysed throughout the 12 months after the liver scan intervention. Costs will be obtained from diagnosis-related group prices obtained from the National Patient Registry for hospital-based services, reimbursement prices obtained from the National Health Service Registry for primary healthcare services and prescription medicine costs from the National Prescription Registry.\u003c/p\u003e\n\u003cp\u003eParticipants\u0026apos; health-related quality of life will be assessed using the validated SF-12 questionnaire at baseline and 6 months after the scan. From the SF-12 questionnaire, data utilities can be derived using a validated conversion algorithm, and quality-adjusted life years (QALYs) will be estimated by multiplying the life years by the utility over the prospective course of 12 months.\u003c/p\u003e\n\u003cp\u003eIndirect societal costs will be estimated from social transfer payments using the DREAM registry\u0026nbsp;(45)\u003c/p\u003e\n\u003cp\u003eA cost-utility analysis will be conducted, analysing the difference in costs divided by the difference in QALYs, comparing the intervention group with the control group at six months.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans to promote participant retention and complete follow-up {18b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe participants are informed orally and in writing about a six-month follow-up by phone. Participants will be contacted by phone up to 10 times within 2 weeks. We expect loss to follow-up to be negligible because we include information from medical chart\u0026nbsp;reviews\u0026nbsp;as well as\u0026nbsp;reviews\u0026nbsp;of charts from Novavi to\u0026nbsp;assess\u0026nbsp;compliance with alcohol treatment. However, if study participants emigrate,\u0026nbsp;they will be regarded as lost to follow-up.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData management {19}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe processing of personal data in the current study will be\u0026nbsp;performed\u0026nbsp;in accordance with the law of data protection,\u0026nbsp;and has received approval from The Danish Data Protection Agency (REG-149-2020).\u0026nbsp;It is the responsibility of the primary investigator to ensure that\u0026nbsp;the\u0026nbsp;handling of personal data will comply with the law of data protection.\u0026nbsp;For\u0026nbsp;the assessment of missing data,\u0026nbsp;see additional file 6.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConfidentiality {27}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBaseline information and the informed consent will be handled in paper form and\u0026nbsp;completed\u0026nbsp;at Novavi K\u0026oslash;ge and Novavi Roskilde,\u0026nbsp;where it will be kept in a locked box in a locked room. Afterwards, the baseline information and informed consent will be transferred safely to the medical department, K\u0026oslash;ge, where the baseline information will be entered into the REDCap (Research Electronic Data Capture) to store the research data safely\u0026nbsp;(46). The remaining documents in paper form\u0026ndash;informed consent and baseline information\u0026ndash;will always be locked safely in a room where only the researchers have access. The 6-month follow-up phone interview will be conducted in a private room, and the results will be entered directly into REDCap. The trial master file is stored on a local secure online platform with a complete audit trail on all data transactions.\u003c/p\u003e\n\u003cp\u003eInterviews with patients for the\u0026nbsp;qualitative\u0026nbsp;study will be audio-recorded with an encrypted voice recorder.\u0026nbsp;The interviews\u0026nbsp;will be transcribed verbatim,\u0026nbsp;and\u0026nbsp;the interviewees\u0026nbsp;will be given pseudonyms. Audio files and transcripts will be stored on a secure drive. The conversion key will be kept separately in paper form in a locked drawer in a locked room.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo specific biological specimens for genetic or molecular analysis were collected for this study. We verified before the start that all the data needed for the analysis were part of the routine blood samples taken at baseline.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical methods\u003c/strong\u003e\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;Statistical methods for primary and secondary outcomes {20a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cu\u003ePrimary outcome\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThe primary outcome (alcohol abstinence or light consumption (\u0026le; 10 units alcohol/week throughout last 30 days) yes/no)\u0026nbsp;will be assessed using logistic regression adjusted for intervention with an invitation to undergo a fibroscan examination and an average number of units per week at inclusion.\u003c/p\u003e\n\u003cp\u003eThe primary outcome will be assessed in the intention-to-treat population and,\u0026nbsp;further, in the per-protocol population. In the latter,\u0026nbsp;the\u0026nbsp;inverse probability of treatment weighting will be used to account for\u0026nbsp;the\u0026nbsp;measured confounding\u0026nbsp;factors\u0026nbsp;of age, sex, average number of drinks per week and months in alcohol abuse treatment.\u0026nbsp;Furthermore, we will analyse whether time in treatment for alcohol use disorder is an effect modifier,\u0026nbsp;analysed as\u0026nbsp;an\u0026nbsp;interaction\u0026nbsp;between\u0026nbsp;randomization group and\u0026nbsp;the\u0026nbsp;primary outcome.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eSecondary outcomes\u003c/u\u003e\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eReduction in\u0026nbsp;the\u0026nbsp;number of heavy drinking days (yes or no)\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eThis secondary outcome will be assessed using\u0026nbsp;logistic\u0026nbsp;regression.\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eReduction in\u0026nbsp;the\u0026nbsp;AUDIT-C score (yes or no, measured on\u0026nbsp;a\u0026nbsp;continuous scale);\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003elinear regression\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eImprovement or no decrease in motivation to\u0026nbsp;reduce\u0026nbsp;alcohol\u0026nbsp;consumption\u0026nbsp;(yes or no)\u0026nbsp;or\u0026nbsp;improvement or no decrease in health-related quality of life (yes or no)\u0026nbsp;are\u0026nbsp;calculated as the difference between baseline and follow-up. Linear regression.\u003c/li\u003e\n \u003cli\u003eStaying in alcohol abuse treatment among participants exceeding light drinking levels (yes/no). Logistic regression.\u003c/li\u003e\n \u003cli\u003eimproving\u0026nbsp;or\u0026nbsp;not decreasing\u0026nbsp;physical or mental health-related quality of life (Sf-12)). Linear regression.\u003c/li\u003e\n \u003cli\u003eimproving\u0026nbsp;or\u0026nbsp;not decreasing\u0026nbsp;smoking Logistic regression.\u003c/li\u003e\n \u003cli\u003eEvaluation of liver disease at the hospital not as part of the study among all participants to assess\u0026nbsp;crossover: whether those\u0026nbsp;randomized\u0026nbsp;as controls had the intervention performed\u0026nbsp;on\u0026nbsp;another occasion (yes/no).\u003c/li\u003e\n \u003cli\u003eComparison within the intervention group:\u0026nbsp;Patients who screened positive\u0026nbsp;were more likely to\u0026nbsp;reduce their\u0026nbsp;alcohol\u0026nbsp;consumption\u0026nbsp;than those who\u0026nbsp;screened\u0026nbsp;negative.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eA statistical analysis plan was uploaded to clinical trials before enrolment began (see additional file 6).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterim analyses {21b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere will be no interim analyses.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods for additional analyses {20b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe will conduct a number of subgroup analyses: compare outcomes between those who screen negative (FibroScan\u0026copy;\u0026nbsp;\u0026lt; 8 kPa) from the intervention group with\u0026nbsp;those from\u0026nbsp;the control group (\u0026ldquo;certificate of health user effect\u0026rdquo;), compare outcomes within participants from the intervention group with a\u0026nbsp;FibroScan\u0026copy;\u0026nbsp;\u0026gt;8 kPa with those from the control group, and\u0026nbsp;compare outcomes\u0026nbsp;by study site, sex, days in alcohol treatment, and others.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods in analysis to handling protocol nonadherence and missing data {20c}.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIf the liver stiffness measurement was not possible due to obesity, etc.,\u0026nbsp;patients will be\u0026nbsp;included in the analysis in addition to the controls.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Participants who are lost to follow-up due to emigration will also be excluded\u0026nbsp;from\u0026nbsp;this analysis. Follow-up will be possible\u0026nbsp;for\u0026nbsp;all other participants (follow-up procedures are described below). A CONSORT flow chart will present the flow of study participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans to give access to the full protocol, participant-level data and statistical code {31c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe full trial protocol is available from clinicaltrials.gov. The dataset from the current study will be available from the corresponding author\u0026nbsp;upon\u0026nbsp;reasonable request.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOversight and monitoring\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComposition of the coordinating centre and trial steering committee {5d}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe trial steering committee\u0026nbsp;(see title page for members) is composed of a principal investigator, lead investigators, a research physician, a data analyst and\u0026nbsp;statisticians. All authors agreed with the final protocol.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComposition of the data monitoring committee and its role and reporting structure {21a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study does not have a data monitoring committee due to the\u0026nbsp;simplicity and low-risk nature of the study. Regular oversight and monitoring will be carried out by the principal investigators to ensure the study\u0026apos;s progress and integrity.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdverse event reporting and harms {22}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTransient elastography is a noninvasive test, and the technique is based on ultrasound. Transient elastography is considered safe without adverse events to the patient\u0026nbsp;(26). The emotional impact of further clinical investigations seems to be negligible, at least after four weeks\u0026nbsp;(16)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFrequency and plans for auditing trial conduct {23}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe intend to perform an audit every eight\u0026nbsp;weeks to review all parts of the research processes, including participant enrolment, consent, eligibility, and allocation to study groups, as well as adherence to trial interventions, reporting of harm, and ensuring the timeliness and accuracy of data collection.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans for communicating important protocol amendments to relevant parties (e.g., trial participants, ethical committees) {25}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe clinical trial registry, sponsors and ethics committee will be notified of any modifications to the trial protocol.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDissemination plans {31a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe trial results will be disseminated to participants, healthcare professionals, the public, and other relevant groups through the publication of peer-reviewed journals and presentations at national and international conferences by the researchers. The results will potentially also be discussed with policymakers to inform political decision-makers about our findings and their potential policy implications.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study has the potential to offer important insights into the efficacy of\u0026nbsp;transient elastography\u0026nbsp;as a screening approach in individuals motivated to achieve alcohol abstinence. Although screening for liver disease in individuals with harmful alcohol consumption is recommended, it remains unclear whether this screening tool is effective in reducing alcohol intake in this specific population\u0026nbsp;(26). One criterion for implementing a screening program is the availability of an accepted treatment for patients with the recognized disease(47). However, without a simple or fast tool available to effectively reduce alcohol intake, the question of whether we have sufficient treatment arises, making this study particularly important. This study aims to investigate whether a screening modality such as FibroScan\u0026copy; can reduce alcohol intake compared to that of patients who do not undergo screening.\u003c/p\u003e\n\u003cp\u003eObservational data suggest that disease screening may serve as a catalyst for behavioural change, which has been observed for tobacco cessation in the setting of lung cancer screening\u0026nbsp;(48)\u0026nbsp;However, no studies have been conducted to investigate this for alcohol and FibroScan\u0026copy; in patients with alcohol use disorder. Therefore, this trial represents the first RCT to examine the effects of FibroScan\u0026copy; screening on alcohol consumption in patients diagnosed with AUD.\u003c/p\u003e\n\u003cp\u003eLimitations:\u003c/p\u003e\n\u003cp\u003eOne potential limitation of the study is the measurement of the primary endpoint, which is alcohol abstinence or light consumption. This registration relies on self-reporting and is retrospective, potentially introducing limitations in reliability. However, this limitation was mitigated by using the timeline follow-back (TLFB) method, which has been extensively tested and evaluated\u0026nbsp;(38). Importantly, as described above, steps will be taken to blind outcome assessors who perform the interviews. To further enhance the accuracy and validity of the data, the information provided will be supplemented and verified with medical and alcohol centre records. This approach ensures a comprehensive assessment of alcohol consumption and reduces the potential influence of social factors and respondent characteristics (such as patients with alcohol dependence tending to portray themselves more negatively in terms of heavy drinking days). If we were to utilize an alcohol marker such as phosphatidyl ethanol for follow-up assessments, we would encounter limitations due to the potential loss to follow-up, primarily consisting of patients who have experienced alcohol relapse, as observed in our pilot project. In this project, it was noted that the individuals we were unable to reach for follow-up indeed experienced relapse, as indicated by their health records.\u003c/p\u003e\n\u003cp\u003eAnother limitation is that the control group receives an intervention that is slightly more active than usual practice, i.e., participants in the control group will be invited to a blood test, whereas in normal circumstances, people need to contact their general practitioner on their own initiative), potentially leading to contamination and blurring the difference between the intervention and control groups. Blood tests are offered to the control group to\u0026nbsp;prevent them from seeking their general practitioner and having blood tests and potentially transient elastography performed elsewhere, which could introduce crossover bias\u0026nbsp;(49).\u003c/p\u003e\n\u003cp\u003eIt should be noted that if the intervention group demonstrates better outcomes, it would be challenging to attribute the results solely to the scanning intervention. This is because the intervention involves a combination of\u0026nbsp;a\u0026nbsp;hospital visit, medical consultation, motivational conversation, and other factors. Therefore, it becomes difficult to isolate the specific contribution of the transient elastography procedure itself in influencing the outcomes.\u003c/p\u003e\n\u003cp\u003eStrengths:\u003c/p\u003e\n\u003cp\u003eSome strengths of this study are the randomized controlled trial design with allocation concealment and the use of three methods for collecting follow-up information, which will minimize loss to follow-up. Additionally, the primary endpoint and follow-up duration, as the choice of using abstinence or light consumption over the last 30 days as the primary endpoint, assessed 6 months after randomization, provide a clinically relevant and meaningful measure of behaviour change.\u003c/p\u003e\n\u003cp\u003eThe use of\u0026nbsp;transient elastography\u0026nbsp;(FibroScan\u0026copy;) as a noninvasive screening tool for liver fibrosis is a significant strength of the study. This approach offers a convenient and relatively low-risk method for detecting liver disease in its early stages compared to the invasive procedure of liver biopsy, potentially enabling early intervention and improved patient outcomes.\u003c/p\u003e\n\u003cp\u003eEmphasis on Alcohol Use Disorder Treatment: By focusing on individuals receiving treatment for alcohol use disorder, the study design targets a population that is more likely to be motivated for alcohol abstinence. This emphasis increases the relevance and potential impact of the findings on clinical practice and patient care in the context of alcohol-related liver disease.\u003c/p\u003e\n\u003cp\u003ePerspectives:\u003c/p\u003e\n\u003cp\u003eThis study has significant implications for the field of alcohol dependence and screening for chronic liver disease. It addresses the crucial question of whether screening for chronic liver disease contributes to better outcomes for individuals with alcohol use disorders.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial status\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStudy protocol version number and date: 02. Version 05.01.2023\u003c/p\u003e\n\u003cp\u003eRecruitment began: May 2023\u003c/p\u003e\n\u003cp\u003eRecrutiment is expected to be completed: November 2026.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSPIRIT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eStandard Protocol Items:Recommendations for Clinical Interventional Studies\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eALD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ealcohol-related liver disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFIB-4\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eFibrosis index based on four factors\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIQR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003einterquartile range\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ekPa\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ekilopascal\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAUDIT C\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAlcohol Use Disorder Identification Test\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSF-12 v2\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eShort-form 12-item scale, version 2\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePSS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePerceived Stress Scale\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecomputed tomography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCOM-B model\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecapability, opportunity, motivation and behaviour model\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eREDCap\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eResearch Electronic Data Capture\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTLFB\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTimeline Follow-Back\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSAP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eStatistical Analysis Plan\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions {31b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePD: Research physician: wrote the draft of\u0026nbsp;the\u0026nbsp;final trial report and contributed to\u0026nbsp;the\u0026nbsp;study design.\u003c/p\u003e\n\u003cp\u003eGA: Principal investigator;\u0026nbsp;PJ: Lead investigator: conceived the study idea, developed\u0026nbsp;the\u0026nbsp;study design, led the proposal and protocol development and reviewed the manuscript.\u003c/p\u003e\n\u003cp\u003eLGM contributed to\u0026nbsp;the\u0026nbsp;study design, development of the protocol, review of the manuscript and\u0026nbsp;was\u0026nbsp;responsible for\u0026nbsp;the\u0026nbsp;hospital study facilities.\u003c/p\u003e\n\u003cp\u003eSD contributed to\u0026nbsp;the\u0026nbsp;study design and review of the manuscript.\u003c/p\u003e\n\u003cp\u003eKB contributed to\u0026nbsp;the\u0026nbsp;study design and review of the manuscript.\u003c/p\u003e\n\u003cp\u003eLM contributed to\u0026nbsp;the\u0026nbsp;study design and review of the manuscript.\u0026nbsp;\u003cbr\u003e\u0026nbsp;MWJ,\u0026nbsp;a lead\u0026nbsp;trial data analyst,\u0026nbsp;developed the statistical analysis plan and reviewed the manuscript.\u003cbr\u003e\u0026nbsp;JCG, a qualitative\u0026nbsp;researcher,\u0026nbsp;contributed to\u0026nbsp;the\u0026nbsp;qualitative study design and review of the manuscript.\u003c/p\u003e\n\u003cp\u003eKJJ\u0026nbsp;was\u0026nbsp;responsible for the health economic impact study.\u003c/p\u003e\n\u003cp\u003eAll the authors have read and approved the final manuscript.\u003cbr\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding {4}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe, the researchers, have initiated the research project, no companies or institutions have initiated the project, and there are no financial or marketing interests associated with the project.\u003c/p\u003e\n\u003cp\u003eGro Askgaard, Zealand University Hospital, received funding from Den f\u0026aelig;llesregionale pulje til forskning i forebyggelse (1.198.000 DKK), Fonden Novavi (900.000 DKK) and the Novo Nordisk Foundation (2.998.000 DKK).\u0026nbsp;This funding will cover salaries for researchers, project nurses, and administrators and will pay for analyses of blood samples. The funders had no role in the research design or decision to publish. Moreover, the researchers in this project have no commitments to the funders.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials {29}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMWJ and JP will have access to the raw\u0026nbsp;dataset. Following the analysis of the primary and secondary outcomes, PD, GA, LGM, and PJ will also be provided access to the dataset.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate {24}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol was approved by The Committee on Health Research Ethics of Region Zealand, Denmark (Project ID: SJ-995, EMN-2022-05916). The protocol is available at clinicaltrials.gov. All patients provided written informed consent and were not offered financial compensation. The study was conducted under the Helsinki Declaration.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication {32}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe results\u0026nbsp;will be published\u0026nbsp;regardless of whether they are\u0026nbsp;positive, negative, or inconclusive via\u0026nbsp;\u003ca href=\"http://www.clinicaltrials.gov\"\u003ewww.clinicaltrials.gov\u003c/a\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests {28}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eChan AW, Tetzlaff JM, Altman DG, Laupacis A, G\u0026oslash;tzsche PC, Krleža-Jerić K et al. SPIRIT 2013 statement: defining standard protocol items for clinical trials. 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Int J Epidemiol [Internet]. 2015 Dec 1 [cited 2024 Jun 10];44(6):2006\u0026ndash;19. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/26377509/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/26377509/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Additional File 4","content":"\u003cp\u003eAdditional File 4 is not available with this version. \u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Alcohol use disorder, screening, alcohol-related liver disease, liver fibrosis, outpatient alcohol treatment, transient elastography, liver stiffness measurement, randomized trial","lastPublishedDoi":"10.21203/rs.3.rs-4609877/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4609877/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eEarly diagnosis of alcohol-related liver disease (ALD) can improve survival if it leads to alcohol abstention or very light consumption. It is possible to screen for liver fibrosis, an asymptomatic condition of ALD that can lead to cirrhosis, by an easy and noninvasive approach called transient elastography. It has not yet been established whether screening for liver fibrosis reduces alcohol consumption among individuals with alcohol use disorders compared to usual treatment. In addition, it is important to address whether receiving a screening result indicating no ALD could lead to increased alcohol consumption (the certificate-of-health effect). This is a protocol for a study that aims to evaluate the efficacy of screening for liver fibrosis with transient elastography on alcohol use outcomes in individuals who are receiving treatment for alcohol use disorder in the community.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThe study follows a randomized, controlled trial design (RCT) with concealed allocation in a 2:1 ratio to the intervention group or the control group. Blinded outcome assessments will be conducted for both parallel groups. A total of 408 patients will be randomized to receive both transient elastography and blood tests (intervention group, n\u0026thinsp;=\u0026thinsp;272) or usual care consisting of a blood test (control group, n\u0026thinsp;=\u0026thinsp;136). The primary outcome will be abstinence or light consumption (\u0026le;\u0026thinsp;10 units per week, 1 unit\u0026thinsp;=\u0026thinsp;12 g alcohol) throughout the last 30 days, as evaluated six months after randomization. Secondary outcomes include health-related quality of life and motivation to reduce alcohol intake. The \u0026ldquo;certificate-of-health effect\u0026rdquo; will be assessed by comparing abstinence or light alcohol consumption after six months between the screen-negative patients and the controls. Additionally, qualitative studies will explore the emotional impact of screening on participants\u0026rsquo; and health professionals\u0026rsquo; barriers to the implementation of screening.\u003c/p\u003e\u003ch2\u003eDiscussion\u003c/h2\u003e \u003cp\u003eThis study has the potential to offer important insights into the effect of screening for liver fibrosis on alcohol consumption among individuals who are attending treatment for alcohol use disorder. Furthermore, the study will provide insights into user and health professionals\u0026rsquo; experiences related to screening.\u003c/p\u003e\u003ch2\u003eTrial registration\u003c/h2\u003e \u003cp\u003eClinicalTrials.gov NCT05855031. Registered on the 20th of April 2023.\u003c/p\u003e","manuscriptTitle":"The Liver Care Trial: Screening for liver disease in individuals attending treatment for alcohol use disorder - study protocol for a randomized controlled study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-28 13:51:28","doi":"10.21203/rs.3.rs-4609877/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revision","date":"2025-05-10T02:12:09+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-08-03T15:05:35+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-08-01T07:08:11+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-07-09T12:07:51+00:00","index":"","fulltext":""},{"type":"submitted","content":"Trials","date":"2024-06-20T03:21:04+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c8eb02ea-6f68-4412-a0bb-4a4207ae4fbd","owner":[],"postedDate":"August 28th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-11-03T16:00:05+00:00","versionOfRecord":{"articleIdentity":"rs-4609877","link":"https://doi.org/10.1186/s13063-025-09151-8","journal":{"identity":"trials","isVorOnly":false,"title":"Trials"},"publishedOn":"2025-10-28 15:57:15","publishedOnDateReadable":"October 28th, 2025"},"versionCreatedAt":"2024-08-28 13:51:28","video":"","vorDoi":"10.1186/s13063-025-09151-8","vorDoiUrl":"https://doi.org/10.1186/s13063-025-09151-8","workflowStages":[]},"version":"v1","identity":"rs-4609877","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4609877","identity":"rs-4609877","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}