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Biomarkers to Predict the Success of Immunosuppression Withdrawal in Autoimmune Hepatitis

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03711669
Recruitment Status : Recruiting
First Posted : October 18, 2018
Last Update Posted : February 12, 2020
Information provided by (Responsible Party):
Maria Londoño, Hospital Clinic of Barcelona

Brief Summary:

Autoimmune hepatitis (AIH) is an inflammatory, chronic and recurrent liver disease of unknown etiology that can lead to cirrhosis or acute liver failure. It is a rare disease affecting 16 cases every 100,000 persons in Europe, mainly in women in every age group. It is characteristic the presence of high levels of aminotransferases, hypergammaglobulinemia and high titres of autoantibodies, as well as interface hepatitis in the biopsy.

Due to the autoimmune etiology of AIH, treatment is based on immunosuppressive strategies, mainly prednisone and azathioprine regimens which make possible to achieve remission in approximately 75% of cases with moderate or severe hepatocellular inflammation.

Remission is defined as a normalization in aminotransferases, immunoglobulin G (IgG) and resolution histological inflammation (this last one comes after biochemical remission). It has also been observed that there is a restoration in number and function of Tregs after achieving remission.

The rates of recurrence after withdrawing it varies from 30-87% depending on the studies and their follow-up. It is usual to maintain treatment indefinitely in clinical practice. This strategy implies maintaining treatment for long periods of time in patients that could be available to maintain sustained remission, exposing them to adverse effects. From all these, we think it is important to be able to identify patients who will be able to maintain biochemical and histological remission without immunosuppression (IS), which still is not known in this disease's management.

Some observational and retrospective studies have identified some parameters that could imply a higher risk of recurrence after stopping treatment such as high levels of aminotransferases and IgG, less time of remission before withdrawal (specifically less than 2 years) or presence of interface hepatitis in a biopsy prior discontinuation of treatment. However, the accuracy of these parameters is low and as a result, management of this disease has not changed much over the past decades, still having patients under prolonged treatment unnecessarily.

For the previously mentioned reasons, there is a need to identify new biomarkers that allow clinicians selecting patients with AIH in whom treatment could be stopped avoiding its costs and adverse effects. At the same time, it would help to understand the immunopathogenesis of AIH and identification of new therapeutic targets.

Condition or disease Intervention/treatment
Autoimmune Hepatitis Behavioral: Immunosuppression withdrawal

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Study Type : Observational
Estimated Enrollment : 96 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Identification of Biomarkers That Help to Predict Success of Immunosuppression Withdrawal in Patients With Type 1 Autoimmune Hepatitis
Actual Study Start Date : January 10, 2018
Estimated Primary Completion Date : January 2021
Estimated Study Completion Date : April 2021

Resource links provided by the National Library of Medicine

Intervention Details:
  • Behavioral: Immunosuppression withdrawal
    IS will be tapered gradually over a period of 6 months. Azathioprine will be stopped during the first 3 months, reducing the dose 50% every month. Prednisone will be tapered 2.5mg monthly until total withdrawal. During withdrawal and the first year after stopping treatment patients will undergo laboratory tests on a monthly basis, afterwards follow-up will be done every 3 months until the end of the project.

Primary Outcome Measures :
  1. Remission rate after treatment withdrawal [ Time Frame: Through study completion (average 1.5 years) ]
    Patients that after stopping treatment maintain aspartate aminotransferase (AST) and alanine aminotransferase (ALT) under 2 times the upper normal limit at the end of the study

Secondary Outcome Measures :
  1. Adverse outcomes after treatment withdrawal (descriptive) [ Time Frame: Through study completion (average 1.5 years) ]
    Evaluation of complications that take place after treatment withdrawal: need of hospitalization if there is a flare or diagnosis of 'de novo' autoimmune diseases or worsening symptoms such as asthenia or arthralgias.

Biospecimen Retention:   Samples With DNA
  • Histological sample at inclusion. The following analysis will be performed: usual staining techniques to evaluate the presence of portal inflammation, interface hepatitis and fibrosis. Expression of group of genes involved in liver rejection (CXCL9, CXCL10, FoxP3, TK1, CD74, MMP9) will be evaluated with qPCR in RNA of the tissue samples cryopreserved at -80ºC. Immunochemical staining to quantity the number of lymphocytes CD4+, CD8+ and Tregs.
  • Blood samples collected at the inclusion and in every follow-up visit:

    • Frequency and characteristics of Tregs (CD4+, CD25+, CD127- and FoxP3). Intracellular stain of CTLA-4 will be evaluated as well
    • Stimulation with IL2 to study Tregs response.
  • Faecal sample at inclusion to evaluate microbiome.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Patients diagnosed with type 1 AIH with biochemical remission of at least 3 years that are under immunosuppressive treatment followed in Hospital Clinic Barcelona. Patients with type 2 AIH are excluded because of their proved high risk of recurrence.

Inclusion Criteria:

  • Diagnosis of type 1 AIH.
  • AST/ALT within normal limits the 3 years prior inclusion.
  • normal levels of IgG.
  • > 18 years-old.

Exclusion Criteria:

  • Presence of biochemical alterations during the 3 years prior diagnosis.
  • Coexistence of another autoimmune disease that requires IS.
  • Prednisone doses over 7.5mg/day.
  • Biopsy prior starting withdrawal with a Knodell score over 3/16.
  • Positivity for hepatitis B virus, hepatitis C virus or human immunodeficiency virus.
  • Pregnancy.
  • Glomerular filtrate <35ml/min.
  • Not being able to attend follow-up visits.
  • Use of drugs or alcohol abuse.

Information from the National Library of Medicine

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

Please refer to this study by its identifier (NCT number): NCT03711669

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Contact: Maria C Londoño, MD,PhD +34 932275753 ext 2845
Contact: Laura P Llovet, MD +34 932275753 ext 2344

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Hospital Clinic Barcelona Recruiting
Barcelona, Spain, 08036
Contact: Maria C Londoño, MD, PhD         
Hospital del Mar Recruiting
Barcelona, Spain
Contact: Montserrat Garcia-Retortillo         
Sponsors and Collaborators
Hospital Clinic of Barcelona
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Principal Investigator: Maria C Londoño, MD, PhD Hospital Clinic of Barcelona
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Responsible Party: Maria Londoño, Senior Staff Specialist, Hospital Clinic of Barcelona Identifier: NCT03711669    
Other Study ID Numbers: PI17/00955
First Posted: October 18, 2018    Key Record Dates
Last Update Posted: February 12, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: IPD are to be shared with researchers participating in the study.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Maria Londoño, Hospital Clinic of Barcelona:
autoimmune hepatitis
disease flare
treatment withdrawal
Additional relevant MeSH terms:
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Hepatitis A
Hepatitis, Autoimmune
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Hepatitis, Chronic
Autoimmune Diseases
Immune System Diseases