TransplantationPhase 4LITENCT02949492
Low-dose IL-2 for Treg Expansion and Tolerance (LITE)
A Phase 4 study testing IL-2 (interleukin 2) in people with Transplantation and Liver Diseases, run by King's College London at 1 site in United Kingdom.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 60 years
- Conditions the study is for
- Transplantation, Liver Diseases
- What is being tested?
- IL-2 (interleukin 2)
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 6 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 12 Dec 2017to 31 Jan 2019
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 60 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: 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.
Read the 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.
- Conditions
- Transplantation, Liver Diseases
- Being tested
- IL-2 (interleukin 2)
- Keywords
- Liver, Transplant, Immunosuppression
- Medical subject headings
- Liver Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
IL-2 (interleukin 2)Drug
Also called Proleukin
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.
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: Drug: IL-2 (interleukin 2) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 12 months post IS withdrawal
Secondary outcomes (2)
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.
Measured: 12 months post IS withdrawal
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.
Measured: 12 months post IS withdrawal
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted31 Oct 2016 (estimated)
- Study start12 Dec 2017
- Primary completion31 Jan 2019
- Study completion31 Jan 2019
Why it stopped: Safety concerns
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for TransplantationStudies of the same condition, open and under way.
- More trials run by King's College LondonThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 6 participants (actual)
Sponsor and investigators
- Lead sponsor
- King's College London
- Sponsor type
- University, hospital or other
- Collaborators
- King's College Hospital NHS Trust
- Responsible party
- Sponsor
- Investigators
- Alberto Sanchez-Fueyo, Principal investigator, King's College London
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02949492
- Sponsor's protocol ID
- LITE-01
- Acronym
- LITE
- Status last verified
- Mar 2018
- First submitted
- 27 Oct 2016
- Last updated
- 14 Aug 2019
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
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.
PubMed 36087863
Study at a glance
From the registry record, last updated by the sponsor on 14 Aug 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Low Dose IL-2 to Expand Endogenous Regulatory T-cells and Achieve Tolerance in Liver Transplantation
- ClinicalTrials.gov ID
- NCT02949492
- Acronym / sponsor ID
- LITE / LITE-01
- Conditions
- Transplantation, Liver Diseases
- Keywords
- Liver, Transplant, Immunosuppression
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Safety concerns
- Enrolment
- 6 participants (actual)
- Lead sponsor
- King's College LondonUniversity, hospital or other
- Collaborators
- King's College Hospital NHS Trust
- Study start
- 12 Dec 2017 (actual)
- Primary completion
- 31 Jan 2019 (actual)
- Study completion
- 31 Jan 2019 (actual)
- First posted
- 31 Oct 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| IL-2 arm | Experimental | Drug: IL-2 (interleukin 2)Liver recipients <50 years old and 2-6 years after transplantation will receive IL-2 and gradually discontinue their immunosuppressive medication |
Who may qualify
- Ages
- 18 to 60 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (5 listed)
- 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.
Key exclusion criteria (2 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| IL-2 (interleukin 2)Also: ProleukinLow-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. | Drug | IL-2 arm |
Primary outcome
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.
2 secondary outcomes
Proportion of tolerant participants remaining free of rejection
Time frame: 12 months post IS withdrawal
Development of serum anti-HLA antibodies
Time frame: 12 months post IS withdrawal
Results and safety
The study was stopped early (reason given: Safety concerns). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Aug 2019.
- Derived from this study: PubMed 36087863Lim 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.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Alberto Sanchez-Fueyo principal investigator
King's College London
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing IL-2 (interleukin 2) in people with Transplantation and Liver Diseases, run by King's College London at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 14 Aug 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Safety concerns). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Discontinuation of immunosuppression drugs (time frame: 12 months post IS withdrawal). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02949492, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Aug 2019.