Low-dose IL-2 for Treg Expansion and Tolerance (LITE) (LITE)
August 12, 2019 updated by: King's College London
Low Dose IL-2 to Expand Endogenous Regulatory T-cells and Achieve Tolerance in Liver Transplantation
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.
Study Overview
Status
Terminated
Conditions
Intervention / Treatment
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
Enrollment (Actual)
6
Phase
- Phase 4
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
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-
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London, United Kingdom, SE5 9RS
- Alberto Sanchez-Fueyo
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Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
18 years to 60 years (ADULT)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
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.
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: TREATMENT
- Allocation: NA
- Interventional Model: SINGLE_GROUP
- Masking: NONE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
|---|---|
|
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
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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 Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
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.
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12 months post IS withdrawal
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
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.
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12 months post IS withdrawal
|
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Development of serum anti-HLA antibodies
Time Frame: 12 months post IS withdrawal
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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.
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12 months post IS withdrawal
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Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Collaborators
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (ACTUAL)
December 12, 2017
Primary Completion (ACTUAL)
January 31, 2019
Study Completion (ACTUAL)
January 31, 2019
Study Registration Dates
First Submitted
October 27, 2016
First Submitted That Met QC Criteria
October 27, 2016
First Posted (ESTIMATE)
October 31, 2016
Study Record Updates
Last Update Posted (ACTUAL)
August 14, 2019
Last Update Submitted That Met QC Criteria
August 12, 2019
Last Verified
March 1, 2018
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- LITE-01
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
UNDECIDED
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
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