Low-dose IL-2 for Treg Expansion and Tolerance (LITE)

NCT02949492 | Terminated Phase 4 DMC

• 1 other identifier: LITE-01
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief Summary

Regulatory T cells (Tregs) suppress cytopathic immune responses and inhibit transplant rejection. Our goal is to exploit the Treg suppressive properties to induce transplantation tolerance. In contrast to effector T cells, Tregs constitutively express the high affinity IL-2 receptor, which makes them exquisitely sensitive to very low-doses of IL-2. We propose here to conduct a phase IV clinical trial in which we will test the capacity of low-dose IL-2 to promote the selective expansion of endogenous Tregs in liver transplant recipients at the time immunosuppressive drugs are being discontinued. We expect this will promote Treg accumulation within the transplanted liver, shift the balance between effector T cells and Tregs, and facilitate the development of operational tolerance in patients unlikely to reach this state spontaneously. We expect the trial to start shortly after the initiation of the project and to provide robust evidence on the efficacy of IL-2 within 47 months.

Conditions

Transplantation; Liver Diseases

Keywords

Liver; Transplant; Immunosuppression

Outcome Measures

Primary Outcomes (1)

• Discontinuation of immunosuppression drugs

  The primary objective is to determine the capacity of a short course of low-dose IL-2 to facilitate the complete discontinuation of immunosuppressive drugs in liver recipients 2-6 years after transplantation.

  12 months post IS withdrawal

Secondary Outcomes (2)

• Proportion of tolerant participants remaining free of rejection

  12 months post IS withdrawal

• Development of serum anti-HLA antibodies

  12 months post IS withdrawal

Study Arms (1)

IL-2 arm

EXPERIMENTAL

Liver recipients \<50 years old and 2-6 years after transplantation will receive IL-2 and gradually discontinue their immunosuppressive medication

Drug: IL-2 (interleukin 2)

Interventions

IL-2 (interleukin 2) DRUG

Low-dose IL-2 will be initiated while study participants remain on a calcineurin inhibitor immunosuppressant. Following 4 weeks of treatment, participants showing at least a 2-fold increase in peripheral blood absolute Treg numbers, stable liver function and no adverse effects will undergo a liver biopsy to exclude sub-clinical graft damage, and subsequently will initiate immunosuppression withdrawal. Low-dose IL-2 will be maintained for a total of 6 months.

Also known as: Proleukin

IL-2 arm

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Adult liver transplant recipients 2-6 years post-transplant and age \<50 years;
• Recipient of single organ transplant only;
• Liver function tests: direct bilirubin and ALT \<2 x ULN at the screening visit;
• On calcineurin inhibitor (CNI) based IS; with or without one of the following: Low dose mycophenolic acid (≤ 1080 mg daily), mycophenolate mofetil (MMF ≤ 1500 mg daily), or azathioprine (≤ 150 mg daily);
• Provision of written informed consent.

You may not qualify if:

• Serum positivity for HCV-RNA at screening; 2. Serum positivity for HIV-1 infection, HBV surface antigen or HBV-DNA at screening; 3. Active liver or systemic immune-mediated disease in which IS discontinuation is inadvisable (autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis); 4. Acute or chronic rejection within the 52 weeks prior to screening; 5. GFR \<40 mL/min (to mitigate the risk of worsening renal failure should rejection occur and high level of CNI be required); 6. The need for chronic anti-coagulation that cannot be safely discontinued to safely perform for a liver biopsy; 7. Screening liver biopsy showing signs of clinically significant histological damage will preclude continuation in the trial; 8. Maintenance immunosuppressive therapy with a mTOR inhibitor (sirolimus or everolimus); 9. Active infection or malignancy; 10. Inability to comply with study directed treatment; 11. Any medical condition that in the opinion of the principal investigator would interfere with safe completion of the trial (including severe cardiac disease, severe respiratory disease with O2 blood saturation \<92%, any other major organ dysfunction, and Eastern Cooperative Oncology Group (ECOG) performance status of ECOG \> 1).
• \. Participation in another IMP study within 3 months from consent; 13. Any known allergy or intolerance to the IMP components; 14. Pregnancy or lactation; 15. Lack of effective methods of contraception for women and men of childbearing potential; 16. Hypersensitivity to Proleukin or to any of the excipients.

Sponsors & Collaborators

• King's College London: lead
• King's College Hospital NHS Trust: collaborator

Study Sites (1)

Alberto Sanchez-Fueyo

London, SE5 9RS, United Kingdom

Location

Related Publications (1)

• Lim TY, Perpinan E, Londono MC, Miquel R, Ruiz P, Kurt AS, Kodela E, Cross AR, Berlin C, Hester J, Issa F, Douiri A, Volmer FH, Taubert R, Williams E, Demetris AJ, Lesniak A, Bensimon G, Lozano JJ, Martinez-Llordella M, Tree T, Sanchez-Fueyo A. Low dose interleukin-2 selectively expands circulating regulatory T cells but fails to promote liver allograft tolerance in humans. J Hepatol. 2023 Jan;78(1):153-164. doi: 10.1016/j.jhep.2022.08.035. Epub 2022 Sep 7.

  PMID: 36087863 DERIVED

MeSH Terms

Conditions

Liver Diseases

Interventions

Interleukin-2; aldesleukin

Condition Hierarchy (Ancestors)

Digestive System Diseases

Intervention Hierarchy (Ancestors)

Interleukins; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Lymphokines; Proteins; Biological Factors

Study Officials

• Alberto Sanchez-Fueyo

  King's College London

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 27, 2016
• First Posted: October 31, 2016
• Study Start: December 12, 2017
• Primary Completion: January 31, 2019
• Study Completion: January 31, 2019
• Last Updated: August 14, 2019

Record last verified: 2018-03

Locations

GB (1)