Belimumab in Autoimmune Hepatitis (BELief)

Belimumab in the Management of Autoimmune Hepatitis: A Multi-centre, Open-label Trial of add-on Belimumab Therapy to Standard of Care

Background: Autoimmune hepatitis (AIH) is a rare chronic and lifelong liver disease. Untreated, disease progresses to end-stage cirrhosis and the focus of therapy is with immunosuppression. Current therapies are limited, not targeted, and associated with side effects that patients report reduce quality of life. AIH is believed to arise as a consequence of genetic & environmental risks. Disease is characterised by impaired immunoregulation, that favours a chronic and relapsing hepatitis. As well as recognising an important role for cytotoxic T cells and regulatory T cells, it has become apparent that in AIH, as well as other related autoimmune conditions, that B-cells are important. AIH is characterised by a plasma cell rich interface hepatitis and elevated IgG concentrations. Furthermore B-cell lineages interact with regulatory T-cells. Off-label use of Rituximab, an anti-CD20 agent, has been described for patients with AIH. A number of other ways of effectively targeting B-cells in the treatment of related autoimmune diseases have also been developed, but there have been limited studies in people living with autoimmune hepatitis. Belimumab is a human monoclonal antibody that inhibits B-cell activating factor (BAFF), also known as B-lymphocyte stimulator. It is approved in the Canada to treat systemic lupus erythematosus and lupus nephritis. It has not been studied before in AIH, but off-label reports are published. In an open-label clinical trial of people living with autoimmune hepatitis, the investigator will now formally study the effect of adding Belimumab to existing standard of care, with the goal being to evaluate treatment efficacy, the ability to reduce the burden of existing therapies whilst still controlling AIH disease, and to describe the tolerability & safety of Belimumab in people with AIH. Study Design: Open label, multi-centre, Canadian clinical trial. Patient population: Patients with autoimmune hepatitis, excluding patients with decompensated liver disease, who either have active disease despite standard of care (Group A), or who are maintained with disease remission using standard of care therapy (Group B). 48 patients will be recruited. Intervention: Weekly sub-cutaneous Belimumab. Duration: 72 weeks with interim analysis after 24 patients have been treated for 24 weeks; target recruitment 48 patients. Evaluation: Safety, Serum liver tests, quality of life, exploratory immunologic biomarkers, optional liver biopsy or fine needle liver aspirate. Primary end-point: Group A: 50% or more of subjects have an ALT<2x ULN & corticosteroids at a dose of </= 5mg of Prednisone (or equivalent); Group B: 50% or more of subjects able to maintain remission (normal ALT, normal IgG) on monotherapy with Belimumab. Conclusion: Using a combination of makers of treatment efficacy and safety the investigator will test the hypothesis that Belimumab should be further formally evaluated for people living with AIH.

Study Overview

• Status: Recruiting
• Conditions: Autoimmune Hepatitis
• Intervention / Treatment: Drug: Belimumab Auto-Injector [Benlysta]

• Study Type: Interventional
• Enrollment (Estimated): 48
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Gideon Hirschfield; Phone Number: 2654 416 340 4800; Email: BELief@uhn.ca

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada
      • Recruiting
      • University Of Calgary
      • Contact: Wilna Bouwer; Phone Number: 403-220-8305; Email: wilna.bouwer@ucalgary.ca
  • British Columbia
    • Vancouver, British Columbia, Canada
      • Recruiting
      • G.I Research Institute
      • Contact: Araceli Wilkinson; Phone Number: 293 604-688-6332; Email: araceliw@giribc.com
  • Ontario
    • Hamilton, Ontario, Canada
      • Recruiting
      • McMaster University
      • Contact: Motunrayo Oyejide; Phone Number: 76986 905-521-2100; Email: oyejidem@mcmaster.ca
    • London, Ontario, Canada
      • Recruiting
      • London Health Sciences Centre
      • Contact: Bedisha Ahmed; Phone Number: 34766 519-685-8500; Email: Bedisha.Ahmed@lhsc.on.ca
    • Toronto, Ontario, Canada, M5G 2C4
      • Recruiting
      • Toronto General Hospital
      • Contact: Gideon Hirschfield; Phone Number: 416-340-4548; Email: gideon.hirschfield@uhn.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Ability to provide written informed consent
• Established clinical diagnosis of autoimmune hepatitis for at least 6 months
• Participant and clinician consent to follow AIH study therapy guidance for the duration of the open label clinical trial.

Group A:

• ALT > 1.5 x ULN in the absence of clinical evidence or concern for alternative etiology, and assessed by the investigator as related to active AIH using standard of care evaluation.
• Ongoing therapy with corticosteroids, and/or non-biologic immunosuppressants (AZA, MMF, MP) at a stable dosage for 4 weeks prior to screening

Group B:

• Patients with normal ALT and normal IgG concentration
• Ongoing therapy with single agent immunosuppression or immunosuppression with low dose Prednisone (10mg or less or budesonide 6mg or less)) alongside a second line agent (azathioprine, MMF, MP)
• Fibroscan showing liver stiffness of < 16kPa.

Exclusion Criteria:

• Primary liver disease other than AIH
• High probability of NAFLD as assessed by the investigator.
• ALT >15 x ULN
• Patients positive for HBsAg or HBcAb and/or Hepatitis C RNA
• Prior use if corticosteroid >15mg daily
• A positive pregnancy test and/or breast feeding

• The presence of advanced liver disease as defined by any of:

  1. Total Bilirubin >3 x ULN.
  2. Platelet count <100 x109/L.
  3. INR >1.5
• Live vaccines within 30 days prior to screening or at any time during the study
• The use of other biologics including TNF inhibitors, abatacept, or tocilizumab within the washout period

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Belimumab; 200mg subcutaneous injection once a week	Drug: Belimumab Auto-Injector [Benlysta]; Belimumab 200 MG/ML [Benlysta] will be given once a week as single-dose autoinjector; Other Names: Benlysta

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To investigate the effect of treatment with Belimumab on AIH disease activity and corticosteroid use in the management of AIH	Group A: Proportion of subjects achieving a response of ALT<1.5x ULN and corticosteroids </= 5mg of Prednisone (or equivalent) Group B: Proportion of subjects able to maintain remission (normal ALT, normal IgG) on monotherapy with Belimumab	Week 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To see the effects of treatment with Belimumab on AIH disease activity and treatment burden	Changes in corticosteroid dose compared to baseline >/= 50% reduction; Changes in corticosteroid dose compared to baseline (expressed as % of initial dosage)	Week 48, Week 72
To measure the effects of Belimumab on markers of AIH disease activity	- Changes in serial biochemistry and IgG compared to baseline	Week 24, Week 48, Week 72
To evaluate the effects of Belimumab on markers of AIH disease activity	- Changes in liver stiffness as measured by elastography compared to baseline	Week 24, Week 48, Week 72
To outline the effects of Belimumab on Patient Reported Outcomes (PRO)	- Change in CLDQ domain scores from Baseline to end of treatment	Week 24, Week 48, Week 72
To assess the effects of Belimumab on Patient Reported Outcomes (PRO)	- Change in Fatigue Scale domain scores from Baseline to end of treatment	Week 24, Week 48, Week 72
To measure the effects of Belimumab on Patient Reported Outcomes (PRO)	- Change in SF-36 domain scores from Baseline to end of treatment	Week 24, Week 48, Week 72
To evaluate the safety of Belimumab in patients with autoimmune hepatitis	- Incidence and frequency of Adverse Events (AEs) and Serious Adverse Events (SAEs) from baseline to end of study.	Week 24, Week 48, Week 72
To assess the safety of Belimumab in patients with autoimmune hepatitis	- Proportion of patients experiencing AE from baseline to end of study.	Week 24, Week 48, Week 72
To report the safety of Belimumab in patients with autoimmune hepatitis	- Change in suicidality score from baseline to end of study	Week 24, Week 48, Week 72
To investigate the effects of treatment with Belimumab on AIH disease activity and treatment burden	Proportion of subjects with ALT<1.5x ULN and able to stop corticosteroids; Proportion of patients with normal ALT, normal IgG and able to stop both corticosteroids and Azathioprine/Mycophenolate Mofetil/6-Mercaptopurine; Proportion of patients with normal ALT, normal IgG and able to stop corticosteroids	Week 48, Week 72
To measure the effects of treatment with Belimumab on AIH disease activity and treatment burden	- Time to biochemical disease relapse (ALT>1.5xULN having reached values <1.5x ULN)	Week 48, Week 72
Safety and Tolerability	Number of participants with treatment-related adverse events as assessed by CTCAE v5.0	Week 24, Week 48, Week 72

Collaborators and Investigators

• Sponsor: University Health Network, Toronto
• Collaborators: GlaxoSmithKline
• Investigators: Principal Investigator: Gideon Hirschfield, MB BChir, PhD, University Health Network, Toronto

Study record dates

Study Major Dates

• Study Start (Actual): December 11, 2024
• Primary Completion (Estimated): April 30, 2028
• Study Completion (Estimated): April 30, 2029

Study Registration Dates

• First Submitted: February 29, 2024
• First Submitted That Met QC Criteria: April 18, 2024
• First Posted (Actual): April 24, 2024

Study Record Updates

• Last Update Posted (Actual): April 24, 2026
• Last Update Submitted That Met QC Criteria: April 21, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Autoimmune Diseases; Immune System Diseases; Digestive System Diseases; Liver Diseases; Hepatitis, Chronic; Hepatitis; Hepatitis, Autoimmune; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; belimumab
• Other Study ID Numbers: 23-5037; 213168 (Other Identifier: Protocol Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No