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.
ID
Source
Brief title
Condition
- Hepatic and hepatobiliary disorders
- Autoimmune disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Difference in proportion of patients with CR at 12 months (normalization of
ALT, AST and IgG) between the TAC and MMF treatment group.
Secondary outcome
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
Background summary
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.
Study 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.
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.
Study burden and risks
The burden of this study consists of:
- 5 visits to the outpatient clinic in a 12 month period
- Extra blood samples will be taken
- 3 fibroscans will be performed
- 3 times patients will be asked to fill in questionnaires regarding quality of
life
Most importantly, patients could reach complete biochemical remission. Complete
biochemical remission is an important treatment goal in autoimmune hepatitis to
prevent further progression to (decompensated) cirrhosis, liver transplantation
or liver related death. Additionally, patients could possibly benefit from
second-line treatment by experiencing a decrease of symptoms.
Risks of the study consist of side-effects of TAC or MMF. As TAC and MMF are
widely used in transplant patients side effects are well known and dose
related. In case of severe side effects the dose can be lowered or study
medication can be discontinued.
Besides side effects, increased immunosuppression could lead to infections.
Several precautions will be taken during the study to minimise the risk.
Patients will be screened for latent infections before the study and other
immunosuppressive medication is stopped.
Albinusdreef 2
Leiden 2333 ZA
NL
Albinusdreef 2
Leiden 2333 ZA
NL
Listed location countries
Age
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 in the past five years, with no history or
current use of chemotherapy.
Design
Recruitment
Medical products/devices used
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2021-003420-33-NL |
| CCMO | NL78216.058.21 |