FXR agonist in post-liver transplantation patients: a randomized open-labeled study.

Anila K N; Saraswathy S Nair; Dinesh Balakrishnan`; Unnikrishnan G; Binoj S T; Ramachandran Narayana Menon; Christi Titus Varghese; Shweta Mallick; Krishnanunni Nair; Madhu Srinivasan Durairaj; Guhan V; Nafiya Zackariah; Haritha Rajakrishnan; Arun Valsan; Johns Shaji Mathew; Cyriac Abby Philips; Christopher Watson; Sudheer O V; Sudhindran S

doi:10.12688/f1000research.159202.2

Home Browse FXR agonist in post-liver transplantation patients: a randomized open-labeled...

ALL Metrics

-

Views

-

Downloads

Get PDF

Get XML

Export

▬

✚

Study Protocol

Revised

FXR agonist in post-liver transplantation patients: a randomized open-labeled study.

[version 2; peer review: 2 approved with reservations]

Anila K N ¹, Saraswathy S Nair¹, Dinesh Balakrishnan`¹, [...] Unnikrishnan G¹, Binoj S T¹, Ramachandran Narayana Menon¹, Christi Titus Varghese¹, Shweta Mallick¹, Krishnanunni Nair¹, Madhu Srinivasan Durairaj¹, Guhan V¹, Nafiya Zackariah¹, Haritha Rajakrishnan¹, Arun Valsan², Johns Shaji Mathew³, Cyriac Abby Philips⁴, Christopher Watson⁵, Sudheer O V¹, Sudhindran S ¹

Anila K N ¹, Saraswathy S Nair¹, [...] Dinesh Balakrishnan`¹, Unnikrishnan G¹, Binoj S T¹, Ramachandran Narayana Menon¹, Christi Titus Varghese¹, Shweta Mallick¹, Krishnanunni Nair¹, Madhu Srinivasan Durairaj¹, Guhan V¹, Nafiya Zackariah¹, Haritha Rajakrishnan¹, Arun Valsan², Johns Shaji Mathew³, Cyriac Abby Philips⁴, Christopher Watson⁵, Sudheer O V¹, Sudhindran S ¹

PUBLISHED 27 Jun 2025

Author details Author details

¹ GI Surgery, Amrita Institute of Medical Sciences & Research Centre, Kochi, Amrita Vishwa Vidyapeetham, Coimbatore, Tamil Nadu, India
² Hepatology, Division of Gastromedicine, Amrita Institute of Medical Sciences & Research Centre, Amrita Vishwa Vidyapeetham, Coimbatore, Tamil Nadu, India
³ Department of Multiorgan transplant and HPB Surgery, Burjeel Hospital, Abu Dhabi, Abu Dhabi, United Arab Emirates
⁴ Department of Clinical and Translational Hepatology, The Liver Institute, Rajagiri Hospital, Aluva, Kerala, India
⁵ Addenbrookes Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 OQQ, UK

Anila K N
Roles: Data Curation, Formal Analysis, Investigation, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing

Saraswathy S Nair
Roles: Data Curation, Methodology

Dinesh Balakrishnan`
Roles: Conceptualization, Supervision, Writing – Review & Editing

Unnikrishnan G
Roles: Conceptualization, Methodology, Supervision, Writing – Review & Editing

Binoj S T
Roles: Writing – Review & Editing

Ramachandran Narayana Menon
Roles: Conceptualization

Christi Titus Varghese
Roles: Writing – Review & Editing

Shweta Mallick
Roles: Writing – Review & Editing

Krishnanunni Nair
Roles: Resources, Writing – Review & Editing

Madhu Srinivasan Durairaj
Roles: Writing – Review & Editing

Guhan V
Roles: Writing – Review & Editing

Nafiya Zackariah
Roles: Methodology

Haritha Rajakrishnan
Roles: Methodology

Arun Valsan
Roles: Writing – Review & Editing

Johns Shaji Mathew
Roles: Conceptualization, Methodology

Cyriac Abby Philips
Roles: Writing – Review & Editing

Christopher Watson
Roles: Writing – Review & Editing

Sudheer O V
Roles: Writing – Review & Editing

Sudhindran S
Roles: Conceptualization, Funding Acquisition, Methodology, Resources, Supervision, Writing – Review & Editing

OPEN PEER REVIEW

REVIEWER STATUS

Abstract

Liver diseases cause nearly 2 million deaths worldwide each year, with approximately 1 million deaths from cirrhosis complications and another 1 million from viral hepatitis and liver cancer, according to WHO estimates. Liver transplantation (LT) remains the primary curative option, boasting success rates of 85% in the first year and 75% at five years post-transplant. Despite high costs, LT is considered cost-effective, especially for younger patients with active work years remaining. However, post-transplant complications, particularly intrahepatic cholestasis, present notable challenges. This complication arises from factors such as ischemia-reperfusion injury, infections, immunological rejection, and surgical complications, all contributing to impaired bile flow and liver damage. Current medical therapies for post-LT cholestasis are limited, with ursodeoxycholic acid (UDCA) frequently used, despite questionable efficacy. Obeticholic acid (OCA), a potent Farnesoid X Receptor (FXR) agonist approved by the FDA for treating primary biliary cholangitis (PBC), has shown potential benefits in reducing elevated cholestatic liver enzymes. Given its significant effects on liver health, OCA may offer therapeutic value in managing post-transplant cholestasis and improving graft survival.

This randomized controlled trial (RCT) aims to evaluate OCA’s efficacy compared to UDCA in reducing cholestatic injury and enhancing graft function post-LT. The primary outcomes will focus on a 15% reduction in alkaline phosphatase and gamma-glutamyl transferase levels at 3, 6, and 12 months from baseline one month. Secondary outcomes include molecular markers, biliary complications, graft rejection, quality of life, and cost-effectiveness. Results are anticipated to demonstrate that OCA could improve graft survival, reduce complications, and enhance quality of life, potentially setting a new standard in post-LT care if found beneficial.

Keywords

Liver transplantation, cholestasis, ursodeoxycholic acid, obeticholic acid, alkaline phosphatase.

Corresponding authors: Anila K N, Sudhindran S

Competing interests: No competing interests were disclosed.

Grant information: This work has recently received seed grant funding from the institution’s Research fund.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright: © 2025 K N A et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: K N A, S Nair S, Balakrishnan` D et al. FXR agonist in post-liver transplantation patients: a randomized open-labeled study. [version 2; peer review: 2 approved with reservations]. F1000Research 2025, 14:9 (https://doi.org/10.12688/f1000research.159202.2) First published: 02 Jan 2025, 14:9 (https://doi.org/10.12688/f1000research.159202.1) Latest published: 27 Jun 2025, 14:9 (https://doi.org/10.12688/f1000research.159202.2)

Revised Amendments from Version 1

This revised version (Version 2) of the article incorporates all the suggestions and recommendations provided by the two reviewers. Based on their valuable feedback, several sections have been revised for clarity, accuracy, and improved scientific rigor. Specific modifications include updates to the methodology for better transparency. We sincerely acknowledge the reviewers’ constructive input, which has significantly enhanced the quality and clarity of the manuscript.

To read any peer review reports and author responses for this article, follow the "read" links in the Open Peer Review table.

Introduction

Liver diseases cause nearly 2 million deaths worldwide each year, with approximately 1 million deaths from cirrhosis complications and another 1 million from viral hepatitis and liver cancer, according to WHO estimates.^1,2 Liver transplantation (LT) is recognized as the primary curative treatment, with success rates reaching 85% in the first year and 75% at 5 years post-transplantation.³ In India, over 3000 liver transplants are performed annually. Despite the considerable expense associated with LT, it is considered cost-effective, especially for individuals in their prime years, who have many active work years ahead of them.^4,5 However, post-transplant morbidity, particularly intrahepatic cholestasis, presents significant challenges.⁶

Intrahepatic cholestasis is a major complication following liver transplantation, caused by multiple factors. Ischemia-reperfusion injury during organ retrieval and transplantation leads to cellular damage and postoperative cholestasis.^7,8 Sepsis from infections worsen cholestasis through inflammatory responses.⁹ Essential post-transplant drugs, including immunosuppressants and antibiotics, can interfere with bile formation, causing liver injury.^10,11 Immunological reactions such as T-cell and B-cell-mediated rejection and lymphocytic cholangitis also contribute to cholestasis.¹² Surgical complications like stenosis or obstruction of the biliary and vascular anastomosis can also result in intra- and extrahepatic cholestasis.^13–15

It is usually administered for three months post-transplant at a dose of 10-15 mg/kg thrice daily. In 2016, the FDA approved obeticholic acid (OCA), a strong selective Farnesoid X Receptor (FXR) agonist, to treat primary biliary cholangitis (PBC) in conjunction with UDCA.^16,17 Research has demonstrated that over 12 months, OCA, either in combination with UDCA or on its own, dramatically lowers levels of total bilirubin and alkaline phosphatase.^18,19 In individuals with advanced liver disease, the FDA has cautioned against administering OCA at doses of 10–50 mg.²⁰ Studies comparing OCA’s effects on cholestasis, rejection, regeneration, and cost-effectiveness to the current standard UDCA are being conducted to assess the role of OCA in the postoperative recovery of liver transplant patients.²¹ Our proposed project is a clinical trial between OCA and the current standard of care, UDCA, in managing post-liver transplant cholestasis and improving graft survival.²²

Rationale

Following LT, a major morbidity mitigating long-term liver functions is intrahepatic cholestasis due to a multitude of reasons. The only drug available for the treatment of intrahepatic cholestasis currently is UDCA.²³ FXR is a newly detected receptor gene, playing multiple roles in liver homeostasis, including detoxification of bile acid excess, stimulation of bile salt export from hepatocytes, reduction of inflammation, delaying fibrosis, and perhaps may even assist liver regeneration.^24,25 A promising alternative is obeticholic acid, that has got its approval by the FDA for cholestatic conditions like primary biliary cholangitis (PBC).²⁶ Research shows OCA significantly reduces key liver enzymes like alkaline phosphatase, gamma glutamyl transferase and total bilirubin in cholestatic liver disease, though its effects specifically in LT patients have not been well-studied.^27,28

This study aims to fill an essential gap by evaluating the efficacy of obeticholic acid compared to ursodeoxycholic acid in managing post-liver transplant cholestasis. By conducting specific biochemical tests to assess cholestasis, this research will provide insights into the effectiveness of OCA relative to the current standard, UDCA.²⁹ Additionally, this study will examine the potential effects of OCA on rejection, tissue regeneration, and cost-effectiveness—areas where knowledge is currently limited.^30,31 The ultimate goal of this study is to determine whether OCA can emerge as a new standard of care in post-LT management, offering cost-effective solutions to enhance long-term outcomes for liver transplant patients.

Primary outcomes

We are assessing the effects of obeticholic acid compared to ursodeoxycholic acid in post-liver transplant patients in ameliorating cholestatic injury with primary endpoints, a 15% reduction in alkaline phosphatase and gamma-glutamyl transferase levels at 3, 6, and 12 months from one-month baseline between groups.

Secondary outcomes

• Assessment of biochemical markers (Liver function tests, metabolic profile, CRP, tacrolimus levels).
• Molecular markers (fibroblast growth factor 19 (FGF-19), transforming growth factor β (TGF-β) level, Cytokeratin 18 level, Serum autotaxin level, Bile Salt Export Pump levels (BSEP), Plasma bile acid levels.
• Biopsy-proven acute or chronic rejection.
• Incidence of biliary complications.
• All-cause mortality.
• Any adverse events.
• Death due to acute or chronic rejection.
• Quality of life.

Methods

This RCT is being conducted in the Department of GI Surgery, Amrita Institute of Medical Sciences, Kochi.

Study design and participants

The study is being conducted as an investigator-initiated, parallel-group, open-label randomized controlled trial in patients undergoing live donor liver transplantation since December 2021 in the Department of Gastrointestinal Surgery at a tertiary care teaching hospital.

Eligibility & exclusion criteria

All adult patients undergoing live donor liver transplantation during the study period are being included. Recipients who are less than 18 years of age, those undergoing deceased donor liver transplants, ABO-incompatible transplants, retransplant cases, those not surviving beyond 30 days, and patients lost to follow-up during the study period, are being excluded. We excluded patients who were randomized into the trial but died within the first 30 days. This decision was based on the fact that early mortality in this period is most commonly attributable to sepsis or technical complications. Including such patients would not be appropriate for evaluating interventions aimed at the management of cholestasis, which usually occur 2 to 3 weeks after surgery. Mortality within 30 days, purely secondary to the adverse effect of the drug, with no other technical (vasculo-biliary), septic or immunological cause is extremely unlikely.

Recruitment & randomization

A clinical pharmacist is randomizing study participants admitted to the GI Surgery ICU following liver transplantation. A permuted block sequence of computer-generated random numbers is being used to enroll subjects into either the control arm (C) or the study arm (T)—i.e., to receive either the standard liver protectant ursodeoxycholic acid [URSETOR^® of Torrent Pharma] 10–15 mg/kg TID (control) or obeticholic acid 5 mg OD [OCANASH^® of Macleods Pharmaceutical Limited]. The sequence is being kept in sealed opaque envelopes and is being opened by the pharmacist on the second day following liver transplantation.

Given the difference in tablet size and dosing frequency (three times daily for UDCA vs once daily for OCA), blinding is not being done.

Follow-up visits for physical examinations and safety assessments are being scheduled during the study period at the following intervals: one month, three months, six months, and twelve months post-transplant ( Figure 1). Liver function tests, C-reactive protein (CRP), platelet count, prothrombin time/international normalized ratio (PT/INR), fasting blood sugar (FBS), tacrolimus concentration, and other relevant parameters are being measured at each follow-up visit. Lipid profile—including total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), very low-density lipoprotein (VLDL), and triglycerides (TG)—as well as glycosylated hemoglobin (HbA1c) levels, are being assessed at pre-transplant admission, and at three, six, and twelve months post-transplant.

Figure 1. Flow chart showing study methodology.

We selected a 15% reduction in both alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) as our primary biochemical endpoint based on evidence from previous trials in cholestatic liver disease. Specifically, the landmark study by Nevens et al., published in The New England Journal of Medicine (2016), evaluated obeticholic acid in patients with primary biliary cholangitis and used a composite endpoint that included a ≥15% reduction in ALP as part of the therapeutic response criteria.

Although this trial was not conducted in post–liver transplant patients, it provided a strong precedent for using ALP-based endpoints to assess treatment response in cholestatic conditions. We extended this rationale by including GGT alongside ALP, as the combination of these two enzymes provides a more comprehensive and sensitive assessment of cholestasis, particularly in the post-transplant setting where bile duct injury and graft function are dynamic.

Given the lack of clinical trials of OCA in the liver transplant population, this combined biochemical endpoint serves as a reasonable and evidence-informed surrogate marker of response in our study.

Secondary endpoint serum markers are being assessed using an enzyme-linked immunosorbent assay (ELISA) [ELK Biotechnology™] at the centralized biochemistry laboratory. Blood samples collected during the one-month and twelfth-month post-transplant follow-up visits are being used for ELISA testing.

In addition, demographics, patient characteristics, and other critical study details (e.g., medication history, medical history, social habits, family history, and use of other medical systems) are being collected through direct patient or bystander interviews, doctor consultation notes, hospital health information systems, and case records. The collected data is being transcribed into a pre-designed proforma (data collection form) by the investigator.

Biopsy and rejection evaluation

A biopsy is being performed when suspected rejection (unexplained rise in transaminases) is observed. The biopsy results are being evaluated based on the Rejection Activity Index score and the Banff criteria. Data on the frequency and duration of the first biopsy-proven acute rejection (BPAR) episode (within six months of transplantation) that requires therapy are being recorded. Any biliary system-related strictures, leaks, or anastomosis issues are being documented. Early allograft dysfunction (EAD) is being assessed using the criteria developed by Olthoff et al.^7,32

Adverse reactions and causality assessment

Adverse events are being captured by direct interview of patients during the routine follow-up visits. We are capturing the pruritus by physical examination, vital signs and 5D pruritus questionnaire and documented systematically using structured Case Report Forms (CRFs) to ensure standardized data collection and analysis. The Naranjo algorithm will be used to establish causality and then classify them as definite, probable, possible, or unlikely.

Quality of life (QOL) measurement

During patient interviews, a validated Chronic Liver Disease Questionnaire (CLDQ) is being administered to assess quality of life (QOL).³³ The copyright license for the English version of the questionnaire is being obtained from the authors. The QOL questionnaire is being completed both pre-transplant and at the one-year post-transplant follow-up. Patients are completing the questionnaire in either Malayalam or English.

The CLDQ includes six domains:

• Abdominal symptoms (AB): Items 1, 5, 17
• Fatigue (FA): Items 2, 4, 8, 11, 13
• Systemic symptoms (SY): Items 3, 6, 21, 23, 27
• Activity (AC): Items 7, 9, 14
• Emotional functions (EM): Items 10, 12, 15, 16, 19, 20, 24, 26
• Worry (WO): Items 18, 22, 25

The CLDQ overall score is the sum of the scores from each domain, ranging from 0 to 203. Lower scores indicate poorer quality of life.

Sample size

The sample size was calculated based on a pilot study comparing the effect of obeticholic acid (OCA) and ursodeoxycholic acid (UDCA) on cholestatic injury in post-liver transplant patients. In the pilot study, the difference in alkaline phosphatase (5.131 ± 39.639 vs 12.496 ± 52.139) was observed between the two groups. With 80% power and 95% confidence, the minimum sample size required was determined to be 108 patients in each group, totaling 216 samples. We will be recruiting around 110 to 120 patients per arm.

Study status

The study is currently in the recruitment phase.

Statistical analysis

• To compare the means of continuous variables between groups (Drug A vs Drug B), an independent sample t-test will be used at each time point.
• To compare the changes in continuous variables from pre- (1 month) to post-transplant (3, 6, and 12 months), a paired t-test will be applied.
• To compare the means of variables from baseline to subsequent time points within each group, repeated measures ANOVA will be used if significant. The Bonferroni multiple comparison test will be applied for pairwise comparisons.

Expected results

We expect a significant reduction in cholestatic liver enzymes following LDLT in the OCA group compared to the UDCA group, with improvements observed from one month to subsequent time points (3, 6, and 12 months). We hypothesize that the potent mechanism of action of OCA will ameliorate cholestatic injury and enhance graft survival. Additionally, we anticipate a reduction in biliary complications, all-cause mortality, and an increase in quality of life for OCA-receiving patients. This may reduce long-term financial expenditure for patients. Given that there are currently no drugs to prevent damage to the transplanted liver, a positive outcome could be a significant advancement for the transplant population. If beneficial, this study could lead to the adoption of OCA as a standard of care following liver transplantation.

Conclusion

Obeticholic acid (OCA) is a farnesoid X receptor (FXR) agonist, with significantly more potency than UDCA in modulating bile acid metabolism. While OCA has shown promise in treating cholestatic liver diseases, its effects post-liver transplantation (LT) remain unclear due to the lack of high-quality trials. Our study aims to evaluate whether OCA’s strong FXR activation can benefit patients with post-LT cholestasis. We hypothesize that OCA will improve graft function, reduce biliary complications, lower associated costs, and enhance overall quality of life and survival for post-LT patients.

Confidentiality

All information about participants enrolled in this clinical trial are treated with the utmost confidentiality to protect their privacy and adhere to ethical standards. Personal identifying information are securely stored and accessible only to authorized personnel involved in the study. Data collected are anonymized and coded to maintain confidentiality during analysis and reporting. Any publication or presentation of results will not include identifiable information unless explicit consent is obtained from participants.

Access to data

Access to data collected during this clinical trial will be managed according to established protocols and regulatory requirements. Authorized personnel, including investigators, statisticians, and regulatory authorities, will have access to raw data for analysis, monitoring, and verification. Data-sharing agreements will be established to govern access by external parties, ensuring compliance with data protection regulations and participant confidentiality. Requests for access to study data from external researchers or institutions will be considered on a case-by-case basis and subject to review by the study sponsor and relevant ethics committees.

Data dissemination

Upon completion of the study, data will be disseminated through peer-reviewed journal publications, conference presentations, and participant communication. Findings will be shared transparently with participants, addressing risks and benefits. Regulatory reporting will ensure compliance with obligations to relevant agencies. Additionally, data-sharing agreements and repositories will facilitate access for other researchers while maintaining participant confidentiality.

Ethical considerations

The study protocol was initially approved by the Institutional Ethics Committee, AIMS (IEC-AIMS-2021-GISURG-262) on 13-10-2021 and later modified for a title change on 15-06-2022 (modified ethics number—IEC-AIMS-2022-GISURG-160). This study involves liver transplant patients aged 18 years or older admitted to our hospital’s gastrointestinal surgery department. Before the study’s initiation, patients gave written informed consent. The consent form was prepared both in English and the local language Malayalam. The study has received ethical clearance from our Institutional Ethics Committee. The committee also approved the informed consent in both languages. This study was registered with the Clinical Trials Registry of India. Our CTRI registration number is CTRI/2021/11/038218 dated on 23/11/2021. The study was conducted according to the principles of the Declaration of Helsinki.

Author contributions

• S. Sudhindran, Unnikrishnan G, Dinesh Balakrishnan, Johns Shaji Mathew, and Shweta Mallick contributed to formulating the concepts.
• Implementation of study including randomization, and data collection: Anila KN, Saraswathy S Nair, Nafiya Zackariah, Haritha Rajakrishnan.
• Drafting manuscript: Anila K N.
• S. Sudhindran, OV Sudheer, Arun Valsan, Binoj ST, Ramachandran Narayana Menon, Krishnanunni Nair, Madhu Srinivasan Durairaj, V Guhan, Christi Titus Varghese contributed to giving valuable inputs and critical revisions.

Data availability statement

No data are associated with this article.

Extended data

Open Science Frame (OSF): FXR agonist in post Liver transplantation patients: A randomized open-labeled study, DOI: 10.17605/OSF.IO/JDXBF³⁴

This project contains the following underlying data:

1. CLD malayalam questionnaire. Pdf
2. CLD QUESTIONNAIRE english.pdf
3. Data collection CRF.pdf
4. Ethics docs.zip
5. Fillable-SPIRIT-Outcomes-2022-Checklist-with-SPIRIT-2013.pdf
6. INFORMED CONSENT DOCUMENT English final.pdf
7. Informed consent Malayalam modified.pdf

Data are available under the terms of the Creative Commons Zero “No Rights Reserved” data waiver (CC0 1.0 Public Domain Dedication).

References

1. World Health Organization: Global health estimates 2020: Deaths by cause, age, sex, by country and by region, 2000-2019. Geneva: WHO; 2020.
2. Mokdad AA, Lopez AD, Shahraz S, et al.: Liver disease burden: global epidemiology and trends. Lancet Gastroenterol. Hepatol. 2020; 5(8): 738–742.
3. Kim WR, Lake JR, Smith JM, et al.: Liver transplantation across the world: results of the international registry. Transplantation. 2022; 106(2): 354–365.
4. Sarin SK, Choudhury A: Liver transplantation in India: challenges and opportunities. J. Clin. Exp. Hepatol. 2021; 11(6): 693–701.
5. Neuberger J, Gilroy R, Baccarani U, et al.: Liver transplantation: economics and outcomes. Hepatology. 2020; 72(3): 1433–1440.
6. Zimmerman HJ: Drug-induced liver disease. Clin. Liver Dis. 2020; 24(3): 631–642.
7. Olthoff KM, Kulik L, Samstein B, et al.: Validation of a definition of early allograft dysfunction in liver transplant recipients and analysis of risk factors. Liver Transpl. 2010; 16(8): 943–949. PubMed Abstract | Publisher Full Text
8. Hirschfield GM, Mason A, Luketic V, et al.: Efficacy of obeticholic acid in patients with primary biliary cholangitis and an inadequate response to ursodeoxycholic acid. Gastroenterology. 2015; 148(4): 751–761.e8. PubMed Abstract | Publisher Full Text
9. FDA: Obeticholic acid (Ocaliva) product label. Silver Spring, MD: U.S. Food and Drug Administration; 2016 [cited 2024 Nov 15]. Reference Source
10. Aron-Wisnewsky J, Clément K, Pépin JL: Nonalcoholic fatty liver disease and obstructive sleep apnea. Metabolism. 2016; 65(8): 1124–1135. Publisher Full Text
11. Younossi ZM, Rinella ME, Sanyal AJ, et al.: Nonalcoholic steatohepatitis: past, present, and future. Hepatology. 2021; 73(Suppl 1): 1194–1198. Publisher Full Text
12. Kowdley KV, Luketic VA, Chapman RW, et al.: A randomized trial of obeticholic acid monotherapy in primary biliary cholangitis. Gastroenterology. 2018; 155(3): 678–689.
13. Bolt MJ, Bergquist A, Verheij J, et al.: Morphological criteria for the diagnosis of lymphocytic cholangitis. Clin. Gastroenterol. Hepatol. 2021; 19(9): 1916–1924.
14. Hirschfield GM, Karlsen TH, Lindor KD, et al.: Primary sclerosing cholangitis. Lancet. 2013; 382(9904): 1587–1599. Publisher Full Text
15. Kulik L, El-Serag HB: Epidemiology and management of hepatocellular carcinoma. Gastroenterology. 2019; 156(2): 477–491.e1. PubMed Abstract | Publisher Full Text | Free Full Text
16. Loomba R, Sanyal AJ: The global NAFLD epidemic. Nat. Rev. Gastroenterol. Hepatol. 2013; 10(11): 686–690. Publisher Full Text
17. FDA: Obeticholic acid: safety announcement for use in advanced liver disease. Silver Spring, MD: U.S. Food and Drug Administration; 2023 [cited 2024 Nov 15]. Reference Source
18. Levy C, Seeff LD, Lindor KD: Use of ursodeoxycholic acid in treating liver disease. Clin. Gastroenterol. Hepatol. 2004; 2(8): 819–827.
19. Trauner M, Fickert P, Wagner M: Bile acids as regulators of hepatic lipid and glucose metabolism. Dig. Dis. 2010; 28(1): 220–224. Publisher Full Text
20. Guicciardi ME, Gores GJ: Apoptosis as a mechanism for liver disease progression. Semin. Liver Dis. 2010; 30(4): 402–410. PubMed Abstract | Publisher Full Text | Free Full Text
21. Dufour JF, Bizzaro N, Cappelletto M, et al.: The clinical use of obeticholic acid in patients with primary biliary cholangitis and advanced liver disease: a multicenter cohort study. J. Hepatol. 2021; 75(3): 687–697.
22. Vargas-Villanueva M, Vasquez-Rios R, Mena J, et al.: Liver transplantation for cirrhosis in Latin America: clinical outcomes and challenges. World J. Hepatol. 2019; 11(5): 303–309.
23. Tapper EB, Sengupta N, Sanyal AJ, et al.: The cost-effectiveness of liver transplantation. Hepatology. 2020; 71(5): 1869–1876.
24. Luetmer PJ, Jensen RT, Cuenco J: Radiologic evaluation of biliary complications following liver transplantation. Radiol. Clin. North Am. 2021; 59(4): 773–786.
25. Mc Hutchison JG, Lawitz EJ, Shiffman ML, et al.: Phase 2 study of obeticholic acid in patients with chronic hepatitis C. Hepatology. 2016; 63(4): 1317–1328.
26. Moretti M, Calvaruso V, Ponziani FR, et al.: Bile acid therapy in liver transplantation: a review of the literature. J. Hepatol. 2021; 75(3): 698–708.
27. Rinella ME, Loomba R, Sanyal AJ, et al.: Efficacy of obeticholic acid in the treatment of nonalcoholic steatohepatitis: a randomized controlled trial. Gastroenterology. 2020; 158(2): 574–584.
28. Gupta A, Suri V, Sharma V, et al.: Obeticholic acid: a review of clinical applications. Indian J. Gastroenterol. 2020; 39(2): 107–115.
29. Singh D, Sood A, Bansal D, et al.: Management of intrahepatic cholestasis after liver transplantation. J. Clin. Exp. Hepatol. 2021; 11(4): 365–375.
30. Geier A, Lohse AW: Treatment of primary biliary cholangitis with obeticholic acid. Hepatology. 2016; 64(2): 492–493.
31. Inoue T, Kondo M, Matsubara T, et al.: The role of bile acid in liver diseases. J. Hepatol. 2020; 72(2): 310–316.
32. Figiel W, Smoter P, Krasnodębski M, et al.: The utility of early allograft dysfunction components in determining 90-day liver graft survival. Transplant. Proc. 2022; 54(4): 1017–1020. PubMed Abstract | Publisher Full Text
33. Younossi ZM, Guyatt G, Kiwi M, et al.: Development of a disease-specific questionnaire to measure health-related quality of life in patients with chronic liver disease. Gut. 1999; 45(2): 295–300. PubMed Abstract | Publisher Full Text | Free Full Text
34. The extended data set of this work is at repository OSF Home. DOI: 10.17605/OSF.IO/JDXBF

Comments on this article Comments (0)

Version 2

VERSION 2 PUBLISHED 02 Jan 2025

Author details Author details

¹ GI Surgery, Amrita Institute of Medical Sciences & Research Centre, Kochi, Amrita Vishwa Vidyapeetham, Coimbatore, Tamil Nadu, India
² Hepatology, Division of Gastromedicine, Amrita Institute of Medical Sciences & Research Centre, Amrita Vishwa Vidyapeetham, Coimbatore, Tamil Nadu, India
³ Department of Multiorgan transplant and HPB Surgery, Burjeel Hospital, Abu Dhabi, Abu Dhabi, United Arab Emirates
⁴ Department of Clinical and Translational Hepatology, The Liver Institute, Rajagiri Hospital, Aluva, Kerala, India
⁵ Addenbrookes Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 OQQ, UK

Anila K N
Roles: Data Curation, Formal Analysis, Investigation, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing

Saraswathy S Nair
Roles: Data Curation, Methodology

Dinesh Balakrishnan`
Roles: Conceptualization, Supervision, Writing – Review & Editing

Unnikrishnan G
Roles: Conceptualization, Methodology, Supervision, Writing – Review & Editing

Binoj S T
Roles: Writing – Review & Editing

Ramachandran Narayana Menon
Roles: Conceptualization

Christi Titus Varghese
Roles: Writing – Review & Editing

Shweta Mallick
Roles: Writing – Review & Editing

Krishnanunni Nair
Roles: Resources, Writing – Review & Editing

Madhu Srinivasan Durairaj
Roles: Writing – Review & Editing

Guhan V
Roles: Writing – Review & Editing

Nafiya Zackariah
Roles: Methodology

Haritha Rajakrishnan
Roles: Methodology

Arun Valsan
Roles: Writing – Review & Editing

Johns Shaji Mathew
Roles: Conceptualization, Methodology

Cyriac Abby Philips
Roles: Writing – Review & Editing

Christopher Watson
Roles: Writing – Review & Editing

Sudheer O V
Roles: Writing – Review & Editing

Sudhindran S
Roles: Conceptualization, Funding Acquisition, Methodology, Resources, Supervision, Writing – Review & Editing

Competing interests

No competing interests were disclosed.

Grant information

This work has recently received seed grant funding from the institution’s Research fund.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Article Versions (2)

version 2

Revised

Published: 27 Jun 2025, 14:9

https://doi.org/10.12688/f1000research.159202.2

version 1

Published: 02 Jan 2025, 14:9

https://doi.org/10.12688/f1000research.159202.1

Copyright

© 2025 K N A et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Download

Export To

metrics

	Views	Downloads
F1000Research	-	-
PubMed Central Data from PMC are received and updated monthly.	-	-

Citations

0

SEE MORE DETAILS

CITE

how to cite this article

K N A, S Nair S, Balakrishnan` D et al. FXR agonist in post-liver transplantation patients: a randomized open-labeled study. [version 2; peer review: 2 approved with reservations]. F1000Research 2025, 14:9 (https://doi.org/10.12688/f1000research.159202.2)

NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.

track

receive updates on this article

Track an article to receive email alerts on any updates to this article.

Open Peer Review

Version 1

VERSION 1

PUBLISHED 02 Jan 2025

Views

12

Reviewer Report 15 May 2025

Gregory Guthrie, Baylor College of Medicine, Houston, Texas, USA

Approved with Reservations

https://doi.org/10.5256/f1000research.174896.r377804

This manuscript addresses an important clinical question: the optimal management of post-liver transplant (LT) cholestasis, comparing Obeticholic Acid (OCA) with the current standard, Ursodeoxycholic Acid (UDCA). The rationale for exploring FXR agonists like OCA in this setting is sound, given ... Continue reading

This manuscript addresses an important clinical question: the optimal management of post-liver transplant (LT) cholestasis, comparing Obeticholic Acid (OCA) with the current standard, Ursodeoxycholic Acid (UDCA). The rationale for exploring FXR agonists like OCA in this setting is sound, given their known roles in bile acid homeostasis, inflammation, and potentially regeneration.
However, for the manuscript to be considered for indexed, several weaknesses need to be addressed, and significant clarifications and additions are required.

Major Weaknesses and Areas Requiring Clarification/Addition:

Study Timeline and Design Clarity (Critical Flaw):
- Contradiction: The "Methods" section states the study "was conducted... from December 2014 to 2021." However, the "Study status" section says, "The study is currently in the recruitment phase." Furthermore, ethics approval is dated 2021/2022, and CTRI registration is from 2021. This is a fundamental contradiction. My understanding is that it is patients that received LT in these years that will be recruited to the study, but the constant change is present and past tense, and the wording makes this unclear. Furthermore, exclusion criteria for patients that died within 30 days would also suggest a difference in timeline, as a patient who died in 2014 after 30 days post LT would certainly not be available to include in a study taking place in 2025. Otherwise, is this exclusion criteria for patients that are started on the study and die within this time frame, in which case this could exclude patients experiencing severe early adverse events or graft failure potentially related to the interventions. A rationale for this exclusion is needed.
Rationale for OCA Dosage and Safety in LT Population:
- FDA Warning Context: The introduction mentions, "In individuals with advanced liver disease, the FDA has cautioned against administering OCA at doses of 10–50 mg." Liver transplant recipients, by definition, have end-stage liver disease pre-transplant and a recovering, vulnerable graft post-transplant. While the study uses 5 mg OD, which is lower, the potential for OCA-related complications (decompensation, worsening LFTs before improvement, severe pruritus) in this specific population needs more thorough discussion.
Primary Endpoint Justification and Baseline:
- 15% Reduction: The primary endpoint is a "15% reduction in alkaline phosphatase and gamma-glutamyl transferase levels." What is the clinical significance of a 15% reduction in these enzymes in post-LT cholestasis? Is this threshold based on previous studies in LT or other cholestatic conditions demonstrating improved long-term outcomes? This needs robust justification.
- One-Month Baseline: The baseline for assessing the primary endpoint is "one-month" post-transplant. Significant cholestasis and LFT fluctuations can occur much earlier post-LT. Why was a 1-month baseline chosen? This might miss early effects or be confounded by stabilization that might occur irrespective of the study drug. A rationale for this time point is crucial.
  - Omission of Bilirubin: Total bilirubin is a key marker of cholestasis severity and liver function. Why is bilirubin not included as a primary or at least a key secondary endpoint for cholestasis assessment?
Sample Size Calculation and Pilot Study Data:
- The pilot study data used for sample size calculation ("difference in alkaline phosphatase (5.131 ± 39.639 vs 12.496 ± 52.139)") shows extremely large standard deviations relative to the means. This suggests massive variability or heterogeneity in the pilot data, or potentially a very small effect size, making the observed difference potentially unreliable for powering a larger trial. A difference of ~7 U/L (assuming these are absolute values) seems very small.
Exclusion Criteria and Analysis Population:
- "patients who discontinued study drugs were excluded." Excluding patients who discontinue the drug from the analysis can introduce significant bias. An intention-to-treat (ITT) analysis, including all randomized patients in the groups to which they were originally assigned, is standard for RCTs and should be the primary analysis. A per-protocol analysis can be secondary. This needs to be specified in the statistical analysis section.
- See earlier comment on exclusion criteria of patients that died <30 days.

Secondary Weaknesses and Areas for Clarification/Addition:

UDCA Dosing:
- - UDCA is dosed at "10-15 mg/kg TID." Typically, UDCA is administered BID in post-transplant settings. Provide a rationale for the TID dosing regimen for UDCA.
Measurement of Specific Secondary Endpoints:
- - "Bile Salt Export Pump levels (BSEP)": How will BSEP levels be measured? Perhaps I am mistaken, but BSEP is a membrane-bound transporter, so will only be measured with biopsies, as in you methods, will only be done in the suspicion of rejection. This is currently too vague.
- "Plasma bile acid levels":
  - Clarification Needed: Will this be total plasma bile acids, or will specific bile acid species be fractionated and quantified (e.g., via LC-MS/MS)? The latter would be much more informative regarding FXR target engagement and changes in bile acid pool composition.
Definition of "Cellular Level" Assessment:
- The Rationale mentions "specific biochemical tests to assess cholestasis at the cellular level."
  - Clarification Needed: Which specific tests (beyond standard LFTs and the listed secondary markers) are being referred to that assess cholestasis at a "cellular level"? This phrasing needs to be more precise or linked directly to specific planned assays (e.g., markers of oxidative stress, apoptosis, or specific transport protein expression if biopsies are analyzed beyond histology).
Introduction and Conclusion Phrasing:
- Introduction: "Although its usefulness is questionable, many practitioners utilize ursodeoxycholic acid (UDCA)..." While there are debates, phrasing it as "questionable" without immediate specific referencing for the LT context might be too strong. Perhaps "its efficacy for preventing all forms of post-LT cholestasis or improving long-term graft survival has limitations" or similar.
- Conclusion: "Obeticholic acid (OCA) is a potent farnesoid X receptor (FXR) agonist, with 100 times the efficacy of the current standard treatment, UDCA..." This is misleading. OCA is ~100 times more potent as an FXR agonist than chenodeoxycholic acid (a primary bile acid), not UDCA. UDCA is not a potent FXR agonist; it has different mechanisms of action (choleretic, cytoprotective, immunomodulatory). This statement needs correction for accuracy.

The study addresses a relevant clinical need. However, the current manuscript contains fundamental inconsistencies and lacks necessary detail and justification in several key areas. Addressing these points comprehensively will be essential for its scientific validity and potential for indexing.

Is the rationale for, and objectives of, the study clearly described?

Yes
Is the study design appropriate for the research question?

Yes
Are sufficient details of the methods provided to allow replication by others?

No
Are the datasets clearly presented in a useable and accessible format?

Partly

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: My research is focused on mechanisms and treatment of cholestatic liver diseases.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

CITE

Report a concern

Respond or Comment

Views

21

Reviewer Report 03 Feb 2025

Palak J Trivedi, University of Birmingham, Birmingham, UK

Approved with Reservations

https://doi.org/10.5256/f1000research.174896.r355921

The rationale for the study is reasonable, but depth of secondary endpoints being captured is limited. Additionally, which adverse events will be captured, in what way, and how will they be recorded?

The dose of UDCA is ... Continue reading

The rationale for the study is reasonable, but depth of secondary endpoints being captured is limited. Additionally, which adverse events will be captured, in what way, and how will they be recorded?

The dose of UDCA is also lower than what would be considered standard practice.

How will pruritus be captured? Highly relevant for OCA-treated patients.

The pivotal phase III trial of obeticholic acid needs to be cited (Nevens et al. NEJM).

As the authors may be aware, the EMA and FDA are in the process of revoking approval for obeticholic acid in Europe and the United States, respectively. Whilst such regulators do not necessarily have jurisdiction in India, how do the authors feel that these decisions will affect access to OCA?

Is the rationale for, and objectives of, the study clearly described?

Yes
Is the study design appropriate for the research question?

Yes
Are sufficient details of the methods provided to allow replication by others?

No
Are the datasets clearly presented in a useable and accessible format?

Partly

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Cholestasis, liver transplantation, clinical trials.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

CITE

Report a concern

Respond or Comment

Comments on this article Comments (0)

Version 2

VERSION 2 PUBLISHED 02 Jan 2025

Open Peer Review

Reviewer Status

Reviewer Reports

	Invited Reviewers
	1	2
Version 2 (revision) 27 Jun 25
Version 1 02 Jan 25	read	read

Palak J Trivedi, University of Birmingham, Birmingham, UK
Gregory Guthrie, Baylor College of Medicine, Houston, USA

Comments on this article

All Comments(0)

Add a comment

Sign up for content alerts

Browse by related subjects

Back to all reports

Reviewer Report

12 Views

15 May 2025 | for Version 1

Gregory Guthrie, Baylor College of Medicine, Houston, Texas, USA

12 Views Cite this report Responses(0)

Approved With Reservations

This manuscript addresses an important clinical question: the optimal management of post-liver transplant (LT) cholestasis, comparing Obeticholic Acid (OCA) with the current standard, Ursodeoxycholic Acid (UDCA). The rationale for exploring FXR agonists like OCA in this setting is sound, given their known roles in bile acid homeostasis, inflammation, and potentially regeneration.
However, for the manuscript to be considered for indexed, several weaknesses need to be addressed, and significant clarifications and additions are required.

Major Weaknesses and Areas Requiring Clarification/Addition:

Study Timeline and Design Clarity (Critical Flaw):
- Contradiction: The "Methods" section states the study "was conducted... from December 2014 to 2021." However, the "Study status" section says, "The study is currently in the recruitment phase." Furthermore, ethics approval is dated 2021/2022, and CTRI registration is from 2021. This is a fundamental contradiction. My understanding is that it is patients that received LT in these years that will be recruited to the study, but the constant change is present and past tense, and the wording makes this unclear. Furthermore, exclusion criteria for patients that died within 30 days would also suggest a difference in timeline, as a patient who died in 2014 after 30 days post LT would certainly not be available to include in a study taking place in 2025. Otherwise, is this exclusion criteria for patients that are started on the study and die within this time frame, in which case this could exclude patients experiencing severe early adverse events or graft failure potentially related to the interventions. A rationale for this exclusion is needed.
Rationale for OCA Dosage and Safety in LT Population:
- FDA Warning Context: The introduction mentions, "In individuals with advanced liver disease, the FDA has cautioned against administering OCA at doses of 10–50 mg." Liver transplant recipients, by definition, have end-stage liver disease pre-transplant and a recovering, vulnerable graft post-transplant. While the study uses 5 mg OD, which is lower, the potential for OCA-related complications (decompensation, worsening LFTs before improvement, severe pruritus) in this specific population needs more thorough discussion.
Primary Endpoint Justification and Baseline:
- 15% Reduction: The primary endpoint is a "15% reduction in alkaline phosphatase and gamma-glutamyl transferase levels." What is the clinical significance of a 15% reduction in these enzymes in post-LT cholestasis? Is this threshold based on previous studies in LT or other cholestatic conditions demonstrating improved long-term outcomes? This needs robust justification.
- One-Month Baseline: The baseline for assessing the primary endpoint is "one-month" post-transplant. Significant cholestasis and LFT fluctuations can occur much earlier post-LT. Why was a 1-month baseline chosen? This might miss early effects or be confounded by stabilization that might occur irrespective of the study drug. A rationale for this time point is crucial.
  - Omission of Bilirubin: Total bilirubin is a key marker of cholestasis severity and liver function. Why is bilirubin not included as a primary or at least a key secondary endpoint for cholestasis assessment?
Sample Size Calculation and Pilot Study Data:
- The pilot study data used for sample size calculation ("difference in alkaline phosphatase (5.131 ± 39.639 vs 12.496 ± 52.139)") shows extremely large standard deviations relative to the means. This suggests massive variability or heterogeneity in the pilot data, or potentially a very small effect size, making the observed difference potentially unreliable for powering a larger trial. A difference of ~7 U/L (assuming these are absolute values) seems very small.
Exclusion Criteria and Analysis Population:
- "patients who discontinued study drugs were excluded." Excluding patients who discontinue the drug from the analysis can introduce significant bias. An intention-to-treat (ITT) analysis, including all randomized patients in the groups to which they were originally assigned, is standard for RCTs and should be the primary analysis. A per-protocol analysis can be secondary. This needs to be specified in the statistical analysis section.
- See earlier comment on exclusion criteria of patients that died <30 days.

Secondary Weaknesses and Areas for Clarification/Addition:

UDCA Dosing:
- - UDCA is dosed at "10-15 mg/kg TID." Typically, UDCA is administered BID in post-transplant settings. Provide a rationale for the TID dosing regimen for UDCA.
Measurement of Specific Secondary Endpoints:
- - "Bile Salt Export Pump levels (BSEP)": How will BSEP levels be measured? Perhaps I am mistaken, but BSEP is a membrane-bound transporter, so will only be measured with biopsies, as in you methods, will only be done in the suspicion of rejection. This is currently too vague.
- "Plasma bile acid levels":
  - Clarification Needed: Will this be total plasma bile acids, or will specific bile acid species be fractionated and quantified (e.g., via LC-MS/MS)? The latter would be much more informative regarding FXR target engagement and changes in bile acid pool composition.
Definition of "Cellular Level" Assessment:
- The Rationale mentions "specific biochemical tests to assess cholestasis at the cellular level."
  - Clarification Needed: Which specific tests (beyond standard LFTs and the listed secondary markers) are being referred to that assess cholestasis at a "cellular level"? This phrasing needs to be more precise or linked directly to specific planned assays (e.g., markers of oxidative stress, apoptosis, or specific transport protein expression if biopsies are analyzed beyond histology).
Introduction and Conclusion Phrasing:
- Introduction: "Although its usefulness is questionable, many practitioners utilize ursodeoxycholic acid (UDCA)..." While there are debates, phrasing it as "questionable" without immediate specific referencing for the LT context might be too strong. Perhaps "its efficacy for preventing all forms of post-LT cholestasis or improving long-term graft survival has limitations" or similar.
- Conclusion: "Obeticholic acid (OCA) is a potent farnesoid X receptor (FXR) agonist, with 100 times the efficacy of the current standard treatment, UDCA..." This is misleading. OCA is ~100 times more potent as an FXR agonist than chenodeoxycholic acid (a primary bile acid), not UDCA. UDCA is not a potent FXR agonist; it has different mechanisms of action (choleretic, cytoprotective, immunomodulatory). This statement needs correction for accuracy.

The study addresses a relevant clinical need. However, the current manuscript contains fundamental inconsistencies and lacks necessary detail and justification in several key areas. Addressing these points comprehensively will be essential for its scientific validity and potential for indexing.

Is the rationale for, and objectives of, the study clearly described?

Yes
Is the study design appropriate for the research question?

Yes
Are sufficient details of the methods provided to allow replication by others?

No
Are the datasets clearly presented in a useable and accessible format?

Partly

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

My research is focused on mechanisms and treatment of cholestatic liver diseases.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

Respond to this report

Responses (0)

Back to all reports

Reviewer Report

21 Views

03 Feb 2025 | for Version 1

Palak J Trivedi, University of Birmingham, Birmingham, UK

21 Views Cite this report Responses(0)

Approved With Reservations

The rationale for the study is reasonable, but depth of secondary endpoints being captured is limited. Additionally, which adverse events will be captured, in what way, and how will they be recorded?

The dose of UDCA is also lower than what would be considered standard practice.

How will pruritus be captured? Highly relevant for OCA-treated patients.

The pivotal phase III trial of obeticholic acid needs to be cited (Nevens et al. NEJM).

As the authors may be aware, the EMA and FDA are in the process of revoking approval for obeticholic acid in Europe and the United States, respectively. Whilst such regulators do not necessarily have jurisdiction in India, how do the authors feel that these decisions will affect access to OCA?

Is the rationale for, and objectives of, the study clearly described?

Yes
Is the study design appropriate for the research question?

Yes
Are sufficient details of the methods provided to allow replication by others?

No
Are the datasets clearly presented in a useable and accessible format?

Partly

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Cholestasis, liver transplantation, clinical trials.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

Respond to this report

Responses (0)

[1] 1. World Health Organization: Global health estimates 2020: Deaths by cause, age, sex, by country and by region, 2000-2019. Geneva: WHO; 2020.

[2] 2. Mokdad AA, Lopez AD, Shahraz S, et al.: Liver disease burden: global epidemiology and trends. Lancet Gastroenterol. Hepatol. 2020; 5(8): 738–742.

[3] 3. Kim WR, Lake JR, Smith JM, et al.: Liver transplantation across the world: results of the international registry. Transplantation. 2022; 106(2): 354–365.

[4] 4. Sarin SK, Choudhury A: Liver transplantation in India: challenges and opportunities. J. Clin. Exp. Hepatol. 2021; 11(6): 693–701.

[5] 5. Neuberger J, Gilroy R, Baccarani U, et al.: Liver transplantation: economics and outcomes. Hepatology. 2020; 72(3): 1433–1440.

[6] 6. Zimmerman HJ: Drug-induced liver disease. Clin. Liver Dis. 2020; 24(3): 631–642.

[7] 7. Olthoff KM, Kulik L, Samstein B, et al.: Validation of a definition of early allograft dysfunction in liver transplant recipients and analysis of risk factors. Liver Transpl. 2010; 16(8): 943–949. PubMed Abstract | Publisher Full Text

[8] 8. Hirschfield GM, Mason A, Luketic V, et al.: Efficacy of obeticholic acid in patients with primary biliary cholangitis and an inadequate response to ursodeoxycholic acid. Gastroenterology. 2015; 148(4): 751–761.e8. PubMed Abstract | Publisher Full Text

[9] 9. FDA: Obeticholic acid (Ocaliva) product label. Silver Spring, MD: U.S. Food and Drug Administration; 2016 [cited 2024 Nov 15]. Reference Source

[10] 10. Aron-Wisnewsky J, Clément K, Pépin JL: Nonalcoholic fatty liver disease and obstructive sleep apnea. Metabolism. 2016; 65(8): 1124–1135. Publisher Full Text

[11] 11. Younossi ZM, Rinella ME, Sanyal AJ, et al.: Nonalcoholic steatohepatitis: past, present, and future. Hepatology. 2021; 73(Suppl 1): 1194–1198. Publisher Full Text

[12] 12. Kowdley KV, Luketic VA, Chapman RW, et al.: A randomized trial of obeticholic acid monotherapy in primary biliary cholangitis. Gastroenterology. 2018; 155(3): 678–689.

[13] 13. Bolt MJ, Bergquist A, Verheij J, et al.: Morphological criteria for the diagnosis of lymphocytic cholangitis. Clin. Gastroenterol. Hepatol. 2021; 19(9): 1916–1924.

[14] 14. Hirschfield GM, Karlsen TH, Lindor KD, et al.: Primary sclerosing cholangitis. Lancet. 2013; 382(9904): 1587–1599. Publisher Full Text

[15] 15. Kulik L, El-Serag HB: Epidemiology and management of hepatocellular carcinoma. Gastroenterology. 2019; 156(2): 477–491.e1. PubMed Abstract | Publisher Full Text | Free Full Text

[16] 16. Loomba R, Sanyal AJ: The global NAFLD epidemic. Nat. Rev. Gastroenterol. Hepatol. 2013; 10(11): 686–690. Publisher Full Text

[17] 17. FDA: Obeticholic acid: safety announcement for use in advanced liver disease. Silver Spring, MD: U.S. Food and Drug Administration; 2023 [cited 2024 Nov 15]. Reference Source

[18] 18. Levy C, Seeff LD, Lindor KD: Use of ursodeoxycholic acid in treating liver disease. Clin. Gastroenterol. Hepatol. 2004; 2(8): 819–827.

[19] 19. Trauner M, Fickert P, Wagner M: Bile acids as regulators of hepatic lipid and glucose metabolism. Dig. Dis. 2010; 28(1): 220–224. Publisher Full Text

[20] 20. Guicciardi ME, Gores GJ: Apoptosis as a mechanism for liver disease progression. Semin. Liver Dis. 2010; 30(4): 402–410. PubMed Abstract | Publisher Full Text | Free Full Text

[21] 21. Dufour JF, Bizzaro N, Cappelletto M, et al.: The clinical use of obeticholic acid in patients with primary biliary cholangitis and advanced liver disease: a multicenter cohort study. J. Hepatol. 2021; 75(3): 687–697.

[22] 22. Vargas-Villanueva M, Vasquez-Rios R, Mena J, et al.: Liver transplantation for cirrhosis in Latin America: clinical outcomes and challenges. World J. Hepatol. 2019; 11(5): 303–309.

[23] 23. Tapper EB, Sengupta N, Sanyal AJ, et al.: The cost-effectiveness of liver transplantation. Hepatology. 2020; 71(5): 1869–1876.

[24] 24. Luetmer PJ, Jensen RT, Cuenco J: Radiologic evaluation of biliary complications following liver transplantation. Radiol. Clin. North Am. 2021; 59(4): 773–786.

[25] 25. Mc Hutchison JG, Lawitz EJ, Shiffman ML, et al.: Phase 2 study of obeticholic acid in patients with chronic hepatitis C. Hepatology. 2016; 63(4): 1317–1328.

[26] 26. Moretti M, Calvaruso V, Ponziani FR, et al.: Bile acid therapy in liver transplantation: a review of the literature. J. Hepatol. 2021; 75(3): 698–708.

[27] 27. Rinella ME, Loomba R, Sanyal AJ, et al.: Efficacy of obeticholic acid in the treatment of nonalcoholic steatohepatitis: a randomized controlled trial. Gastroenterology. 2020; 158(2): 574–584.

[28] 28. Gupta A, Suri V, Sharma V, et al.: Obeticholic acid: a review of clinical applications. Indian J. Gastroenterol. 2020; 39(2): 107–115.

[29] 29. Singh D, Sood A, Bansal D, et al.: Management of intrahepatic cholestasis after liver transplantation. J. Clin. Exp. Hepatol. 2021; 11(4): 365–375.

[30] 30. Geier A, Lohse AW: Treatment of primary biliary cholangitis with obeticholic acid. Hepatology. 2016; 64(2): 492–493.

[31] 31. Inoue T, Kondo M, Matsubara T, et al.: The role of bile acid in liver diseases. J. Hepatol. 2020; 72(2): 310–316.

[32] 32. Figiel W, Smoter P, Krasnodębski M, et al.: The utility of early allograft dysfunction components in determining 90-day liver graft survival. Transplant. Proc. 2022; 54(4): 1017–1020. PubMed Abstract | Publisher Full Text

[33] 33. Younossi ZM, Guyatt G, Kiwi M, et al.: Development of a disease-specific questionnaire to measure health-related quality of life in patients with chronic liver disease. Gut. 1999; 45(2): 295–300. PubMed Abstract | Publisher Full Text | Free Full Text

[34] 34. The extended data set of this work is at repository OSF Home. DOI: 10.17605/OSF.IO/JDXBF

FXR agonist in post-liver transplantation patients: a randomized open-labeled study.

Abstract

Abstract

Keywords

Revised Amendments from Version 1

Introduction

Rationale

Primary outcomes

Secondary outcomes

Methods

Study design and participants

Eligibility & exclusion criteria

Recruitment & randomization

Figure 1. Flow chart showing study methodology.

Biopsy and rejection evaluation

Adverse reactions and causality assessment

Quality of life (QOL) measurement

Sample size

Study status

Statistical analysis

Expected results

Conclusion

Confidentiality

Access to data

Data dissemination

Ethical considerations

Author contributions

Data availability statement

Extended data

References

Comments on this article Comments (0)

Open Peer Review

Comments on this article Comments (0)

Open Peer Review

Reviewer Status

Reviewer Reports

Comments on this article

Browse by related subjects

Competing Interests Policy

Stay Updated