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

• ClinicalTrials.gov Identifier: NCT02949492
• Recruitment Status: Terminated
• First Posted: October 31, 2016
• Last Update Posted: August 14, 2019
• Sponsor: King's College London
• Collaborator: King's College Hospital NHS Trust
• Information provided by (Responsible Party): King's College London

Tracking Information

• First Submitted Date: October 27, 2016
• First Posted Date: October 31, 2016
• Last Update Posted Date: August 14, 2019
• Actual Study Start Date: December 12, 2017
• Actual Primary Completion Date: January 31, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 27, 2016)

Discontinuation of immunosuppression drugs [ Time Frame: 12 months post IS withdrawal ]

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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: October 27, 2016)

• Proportion of tolerant participants remaining free of rejection [ Time Frame: 12 months post IS withdrawal ]
  Measures of rejection in patients (incidence, severity, timing, steroid resistant rejection, chronic rejection) and to investigate if liver transplant recipients under IS become operationally tolerant over time.
• Development of serum anti-HLA antibodies [ Time Frame: 12 months post IS withdrawal ]
  To determine if the presence of donor-specific anti-HLA antibodies influence the success of IS withdrawal, and whether IS withdrawal promotes the development of anti-HLA antibodies in liver transplant recipients.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Low-dose IL-2 for Treg Expansion and Tolerance (LITE)
• Official Title: Low Dose IL-2 to Expand Endogenous Regulatory T-cells and Achieve Tolerance in Liver Transplantation
• 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.
• Detailed Description: Transplantation remains the most successful treatment for end-stage organ failure, but the need to administer life-long immunosuppression (IS) to prevent rejection limits patient survival. Liver transplantation is the only transplantation setting in which a sizeable proportion of patients spontaneously develop "operational tolerance", a phenomenon defined by the maintenance of stable graft function in the absence of destructive immune responses without the need of IS. Unfortunately this phenomenon preferentially develops in elderly recipients and several years after transplantation. To maximize the benefit derived from IS discontinuation there is a need to find strategies to intentionally induce tolerance in young recipients in whom accumulated IS toxicity has not yet occurred. Our studies have revealed that successful IS discontinuation is associated with a transient intra-graft immune regulatory response with preferential accumulation of regulatory T cells (Tregs). This suggests that short-term enhancement of Treg numbers and/or function at the time of IS withdrawal may facilitate the acquisition of tolerance in patients who are not predisposed to spontaneously develop it. IL-2 is a cytokine that is essential for the optimal development, survival and function of Tregs. Several clinical studies have shown that low-dose IL-2 preferentially expands Tregs and is safe and efficacious in patients with autoimmunity or GVHD. In these studies, Treg frequency increased up to 2 to 8-fold without significant changes in the number of effector T cells. Our objective is to investigate if administration of a short-course of low dose IL-2 to liver transplant recipients facilitates the discontinuation of IS. We propose to conduct a phase II, safety and efficacy, prospective, single-arm clinical trial in which liver recipients <50 years old and 2-6 years after transplantation will receive IL-2 and gradually discontinue their IS medication.
• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Transplantation
• Liver Diseases

Intervention

Drug: IL-2 (interleukin 2)

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.

Other Name: Proleukin

Study Arms

Experimental: IL-2 arm

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

Intervention: Drug: IL-2 (interleukin 2)

• Publications *: 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.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: August 12, 2019): 6
• Original Estimated Enrollment (submitted: October 27, 2016): 25
• Actual Study Completion Date: January 31, 2019
• Actual Primary Completion Date: January 31, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Adult liver transplant recipients 2-6 years post-transplant and age <50 years;
2. Recipient of single organ transplant only;
3. Liver function tests: direct bilirubin and ALT <2 x ULN at the screening visit;
4. 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);
5. Provision of written informed consent.

Exclusion Criteria:

1.1. 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).

12. 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 60 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United Kingdom

Administrative Information

• NCT Number: NCT02949492
• Other Study ID Numbers: LITE-01
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: King's College London
• Original Responsible Party: Same as current
• Current Study Sponsor: King's College London
• Original Study Sponsor: Same as current
• Collaborators: King's College Hospital NHS Trust

Investigators

• Principal Investigator: Alberto Sanchez-Fueyo; King's College London

• PRS Account: King's College London
• Verification Date: March 2018