Biomarkers to Predict the Success of Immunosuppression Withdrawal in Autoimmune Hepatitis

NCT03711669 | Unknown

• 1 other identifier: PI17/00955
• Study Type: observational
• Target: 96
• Locations: 1 country
• Sites: 2

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.

Conditions

Autoimmune Hepatitis

Keywords

autoimmune hepatitis; disease flare; treatment withdrawal

Outcome Measures

Primary Outcomes (1)

• Remission rate after treatment withdrawal

  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

  Through study completion (average 1.5 years)

Secondary Outcomes (1)

• Adverse outcomes after treatment withdrawal (descriptive)

  Through study completion (average 1.5 years)

Interventions

Immunosuppression withdrawal BEHAVIORAL

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.

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• 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.

You may qualify if:

• Diagnosis of type 1 AIH.
• normal levels of IgG.
• \> 18 years-old.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Hospital Clinic of Barcelona: lead

Study Sites (2)

Hospital Clinic Barcelona

Barcelona, 08036, Spain

RECRUITING

Hospital del Mar

Barcelona, Spain

RECRUITING

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.

MeSH Terms

Conditions

Hepatitis, Autoimmune

Condition Hierarchy (Ancestors)

Hepatitis, Chronic; Hepatitis; Liver Diseases; Digestive System Diseases; Autoimmune Diseases; Immune System Diseases

Study Officials

• Maria C Londoño, MD, PhD

  Hospital Clinic of Barcelona

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Maria C Londoño, MD,PhD

CONTACT

+34 932275753; mlondono@clinic.cat

Laura P Llovet, MD

CONTACT

+34 932275753; llovet@clinic.cat

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Senior Staff Specialist

Study Record Dates

• First Submitted: October 4, 2018
• First Posted: October 18, 2018
• Study Start: January 10, 2018
• Primary Completion: January 1, 2021
• Study Completion: April 1, 2021
• Last Updated: February 12, 2020

Record last verified: 2020-02

Data Sharing

• IPD Sharing: Will not share

Locations

ES (2)