Back to resultsLow-dose IL-2 for Treg Expansion and Tolerance (LITE) (LITE)
Primary Purpose
Transplantation, Liver Diseases
Status
Terminated
Phase
Phase 4
Locations
United Kingdom
Study Type
Interventional
Intervention
IL-2 (interleukin 2)
Sponsored by
About this trial
This is an interventional treatment trial for Transplantation focused on measuring Liver, Transplant, Immunosuppression
Eligibility Criteria
Inclusion Criteria:
- 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.
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.
Sites / Locations
- Alberto Sanchez-Fueyo
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
IL-2 arm
Arm Description
Liver recipients <50 years old and 2-6 years after transplantation will receive IL-2 and gradually discontinue their immunosuppressive medication
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
Proportion of tolerant participants remaining free of rejection
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
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.
Full Information
NCT ID
NCT02949492
First Posted
October 27, 2016
Last Updated
August 12, 2019
Sponsor
King's College London
Collaborators
King's College Hospital NHS Trust
1. Study Identification
Unique Protocol Identification Number
NCT02949492
Brief Title
Low-dose IL-2 for Treg Expansion and Tolerance (LITE)
Acronym
LITE
Official Title
Low Dose IL-2 to Expand Endogenous Regulatory T-cells and Achieve Tolerance in Liver Transplantation
Study Type
Interventional
2. Study Status
Record Verification Date
March 2018
Overall Recruitment Status
Terminated
Why Stopped
Safety concerns
Study Start Date
December 12, 2017 (Actual)
Primary Completion Date
January 31, 2019 (Actual)
Study Completion Date
January 31, 2019 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
King's College London
Collaborators
King's College Hospital NHS Trust
4. Oversight
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
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Transplantation, Liver Diseases
Keywords
Liver, Transplant, Immunosuppression
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
6 (Actual)
8. Arms, Groups, and Interventions
Arm Title
IL-2 arm
Arm Type
Experimental
Arm Description
Liver recipients <50 years old and 2-6 years after transplantation will receive IL-2 and gradually discontinue their immunosuppressive medication
Intervention Type
Drug
Intervention Name(s)
IL-2 (interleukin 2)
Other Intervention Name(s)
Proleukin
Intervention Description
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.
Primary Outcome Measure Information:
Title
Discontinuation of immunosuppression drugs
Description
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.
Time Frame
12 months post IS withdrawal
Secondary Outcome Measure Information:
Title
Proportion of tolerant participants remaining free of rejection
Description
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.
Time Frame
12 months post IS withdrawal
Title
Development of serum anti-HLA antibodies
Description
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.
Time Frame
12 months post IS withdrawal
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
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.
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Alberto Sanchez-Fueyo
Organizational Affiliation
King's College London
Official's Role
Principal Investigator
Facility Information:
Facility Name
Alberto Sanchez-Fueyo
City
London
ZIP/Postal Code
SE5 9RS
Country
United Kingdom
12. IPD Sharing Statement
Plan to Share IPD
Undecided
Citations:
PubMed Identifier
36087863
Citation
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.
Results Reference
derived
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Low-dose IL-2 for Treg Expansion and Tolerance (LITE)
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