Tacrolimus Versus Mycophenolate for Autoimmune Hepatitis Patients With Incomplete Response on First Line Therapy

Autoimmune Hepatitis Clinical Trial

— TAILOR  

Official title:

TAILOR Study: Tacrolimus Versus Mycophenolate for Autolmmune Hepatitis Patients With incompLete Response On First Line Therapy: a Randomized Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05221411
• Other study ID #: P21.089
• Secondary ID: 2021-003420-33NL
• Status: Recruiting
• Phase: Phase 4
• Start date: January 19, 2022
• Est. completion date: January 2024

Study information

• Verified date: January 2022
• Source: Leiden University Medical Center
• Contact: Anna Stoelinga
• Phone: +31 6 30 29 11 71
• Email: a.e.c.stoelinga[@]lumc.nl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Rationale: The combination of azathioprine and prednisone is the first-line treatment for autoimmune hepatitis (AIH), a chronic inflammatory disease of the liver. Complete biochemical remission (CR) is the first treatment goal in autoimmune hepatitis. CR is determined by AST and ALT and IgG within the reference range. CR is not reached in a substantial proportion of AIH patients: after one year 50%, after three years around 20% did not achieve CR. Without CR ongoing hepatitis leads to progression towards fibrosis and eventually (decompensated) cirrhosis. Not achieving CR is the most important risk factor for the need for liver transplantation or liver related death, independent of age and presence of cirrhosis. Tacrolimus (TAC) and mycophenolate mofetil (MMF) are frequently used to prevent rejection in kidney and liver transplant patients. In AIH patients with insufficient response or intolerance to first-line therapy in retrospective cohort studies with MMF 0-57% and with TAC 20-95% CR was reached.

Objective: The aim of this study is to compare the effectiveness of TAC with MMF as a second line treatment for AIH. Proportion of patients with CR after 12 months of treatment will be the primary outcome parameter to determine effectivity.

Study design: Randomized open-label two arm study. Patients will be randomized between treatment with TAC or MMF.

Study population: Patients with AIH with an incomplete response (no CR) to first-line treatment are eligible for this study.

Intervention: In the TAC group baseline treatment will be replaced by tacrolimus. In the MMF group baseline treatment will be replaced by MMF. The current dose of prednisolone, or at least 5 mg daily, will be continued in both arms. After achieving CR prednisolone will be tapered according to protocol.

Main study parameters/endpoints: Difference in proportion of patients with CR at 12 months (normalization of ALT, AST and IgG) between the TAC and MMF treatment group.

Secondary parameters:

• Safety and tolerability of TAC and MMF treatments

• Difference in proportion of patients with CR at 6 months (normalization of ALT, AST and IgG) between the TAC and MMF treatment group.

• Difference in ALT, AST and IgG at 6 and 12 months versus baseline

• Difference in fibrogenesis and fibrosis parameters between groups and before and after treatment

• Difference in quality of life between groups and before and after treatment

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 86
• Est. completion date: January 2024
• Est. primary completion date: January 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patient is older than 18 years old

• Probable or definite auto immune hepatitis according to the original or simplified IAIHG criteria (>10 points pre-treatment on the original criteria or >6 points on the simplified criteria)(2, 3)

• Incomplete responder on at least a half year of first-line treatment, with at least last 6 months azathioprine / 6-MP) / 6-TG and prednisolone or budesonide, and ALT 1.5
• 10x ULN for at least 2 months

• Patient is capable of understanding the purpose and risks of the study, has been fully informed and has given written informed consent to participate in the study

Exclusion Criteria:

• Presence of decompensated liver disease, defined as ascites, coagulopathy (INR >1.5), encephalopathy, variceal bleed, hepatopulmonal syndrome, hepatorenal syndrome or HCC in the past 6 months

• Signs of other liver diseases as NAFLD, Wilson disease, hemochromatosis, alcoholic liver disease or hepatitis B/C/D

• Clinical diagnosis of overlap / variant syndrome with PBC or PSC

• Liver transplantation in the medical history or currently on the waiting list for liver transplantation

• Incompliance with therapy during the last 12 months

• Active infections during inclusion including latent tuberculosis and HIV co-infection

• Allergic or hypersensitive to tacrolimus or MMF

• An estimated glomerular filtration rate (eGFR) of <60 mL/min

• Pregnancy or intention to become pregnant in the next 12 months

• Use of TAC or MMF in the past

• Malignancy in the medical history

Related Conditions & MeSH terms

• Autoimmune Hepatitis
• Hepatitis
• Hepatitis A
• Hepatitis, Autoimmune

Intervention

Drug:
• Mycophenolate Mofetil
Mycophenolate mofetil will be started at a dose 500mg twice daily. When tolerated and an AUC within range, patients will be titrated to 1000mg twice daily at week two.
• Tacrolimus
Meltdose tacrolimus will be started at a dose of 0.07 mg/kg/day. The drug will be taken orally once-daily in the morning. Dose will be adjusted to reach target AUC and trough levels.

Locations

Country	Name	City	State
Netherlands	Reinier de Graaf Gasthuis	Delft
Netherlands	Jeroen Bosch Ziekenhuis	Den Bosch
Netherlands	Medisch Spectrum Twente	Enschede
Netherlands	Leiden University Medical Center	Leiden
Netherlands	Maastricht University Medical Center +	Maastricht
Netherlands	University Medical Center Utrecht	Utrecht

Sponsors (1)

Lead Sponsor	Collaborator
Leiden University Medical Center

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Complete biochemical remission	The proportion of patients with CR after 12 months of treatment with TAC compared to MMF in patients with AIH with an incomplete response to first-line treatment.	52 weeks
Secondary	Safety and Tolerability	Number and severity of side effects; Rate of stopping treatment due to side effects; serum creatinin & potassium; Blood pressure; Blood glucose levels and incidence of new onset diabetes; Number of (opportunistic) infections; tremor; diarrhea	52 weeks
Secondary	Proportion of patients with complete biochemical remission after 6 months	Defined as ALT, AST and IgG below the upper limit of normal	24 weeks
Secondary	Proportion of patients with partial response	defined as decrease of AST and ALT, but no normalization	52 weeks
Secondary	Proportion of patients with insufficient treatment response	less than 25% reduction in ALT after 6 and 12 months treatment	52 weeks
Secondary	Dose reduction of prednisone	Difference between dose at inclusion and dose at the end of study	52 weeks
Secondary	Cessation rate of prednisone	The number of patients able to completely withdraw from corticosteroids	52 weeks
Secondary	Change of AST	at 6 and 12 months versus baseline and between groups at the same time points	24 and 52 weeks
Secondary	Change of ALT	at 6 and 12 months versus baseline and between groups at the same time points	24 and 52 weeks
Secondary	Change of IgG	at 6 and 12 months versus baseline and between groups at the same time points	24 and 52 weeks
Secondary	Liver function	Total bilirubin, albumin, INR and MELD-score after 6 and 12 months between groups	24 and 52 weeks
Secondary	Fibrosis	Liver stiffness as measured by elastography and blood fibrosis markers (ELF)	52 weeks
Secondary	Influence of liver disease on the quality of life	using the validated liver disease symptom index (LDSI)	52 weeks
Secondary	Treatment effect on health status	using the validated EQ5D	52 weeks
Secondary	Cost-effectiveness based on empiric data obtained by this study.	Economic evaluation including a cost-effectiveness evaluation	52 weeks
Secondary	Cost-effectiveness from a societal perspective	Economic evaluation including a cost-utility evaluation (costs per QALY)	52 weeks