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Type 1 Diabetes MellitusPhase 1TILTNCT02772679

T1DM Immunotherapy Using Polyclonal Tregs + IL-2

A Phase 1 study testing PolyTregs+IL-2 in people with Type 1 Diabetes Mellitus, run by Jeffrey Bluestone at 2 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

The purpose of this study is to assess the safety of Tregs + IL-2 and survival of Tregs in patients with recent onset T1DM who receive infusions of autologous Tregs + IL-2. Read more about this study

Who is it for?
Ages 18 to 45 years
Conditions the study is for
Type 1 Diabetes Mellitus
What is being tested?
PolyTregs+IL-2
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
16 participants
Where
2 sitesUnited States
Study dates
Aug 2016to 27 Aug 2021
Phase
Phase 1
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 45 years
  • All sexes
  • No healthy volunteers
  • Adult

Who may be able to join

  • Diagnosis of T1DM within >3 and <24 months of day 0 according to the American Diabetes Association standard criteria.
  • 18 to 45 years of age on day of screening visit.
  • Positive for at least one islet cell autoantibody (glutamate decarboxylase; insulin, if obtained within 10 days of the onset of insulin therapy; ICA 512-antibody; and/or ZnT8).
  • Peak stimulated C-peptide level >0.2 pmol/mL (0.6 ng/ml) following an MMTT.
  • Weight of >= 40 kg and <=90.7kg
  • Adequate venous access to support a blood draw of 5 mls/kg up to maximum of 400 ml whole blood and later infusion of investigational therapy

Who cannot join

  • Hemoglobin <10.0 g/dL; leukocytes <3,000/μL; neutrophils <1,500/μL; lymphocytes <800μL; platelets <100,000/μL
  • Any sign of significant chronic active infection (e.g., hepatitis, tuberculosis, EBV, or CMV), or screening laboratory evidence consistent with a significant chronic active infection (such as positive for HIV, PPD, or HBsAg).
  • Anticipated ongoing use of diabetes medications other than insulin that affect glucose homeostasis, such as metformin, sulfonylureas, thiazolidinediones, glucagon-like peptide 1 (GLP-1) mimetics, dipeptidyl peptidase IV (DPP-IV) inhibitors, SGLT2 inhibitors, or amylin.
  • Chronic use of systemic glucocorticoids or other immunosuppressive agents, or biologic immunomodulators within 6 months prior to study entry. Specifically, subjects who have received over 7 days of treatment with 7.5 mg of prednisone (or the equivalent) within 6 months prior to study entry will be excluded.
  • History of malignancy (including squamous cell carcinoma of the skin or cervix) except adequately treated basal cell carcinoma
  • Pregnant or breastfeeding women, or any female who is unwilling to use a reliable and effective form of contraception for 1 year after Treg +/- IL-2 dosing, and any male who is unwilling to use a reliable and effective form of contraception for 3 months after Treg +/- IL-2 dosing
  • Any condition that, in the investigator's opinion, may compromise study participation or may confound the interpretation of the study results.
  • Patients who are unwilling to agree to not participate in another clinical trial, which in the opinion of the investigator may confound the results of this study, for at least 1 year following Treg infusion.

Trial locations and contacts

2 sites in 1 country.

United States2 sites

  • Yale University

    New Haven, Connecticut, 06519

  • University of California, San Francisco Medical Center

    San Francisco, California, 94143

Other trials in United States

About this study

Official title: A Phase 1 Trial of CD4+CD127lo/-CD25+ Polyclonal Treg Adoptive Immunotherapy With Interleukin-2 for the Treatment of Type 1 Diabetes

The purpose of this study is to assess the safety of Tregs + IL-2 and survival of Tregs in patients with recent onset T1DM who receive infusions of autologous Tregs + IL-2.

Read the detailed description

The investigators hypothesize that ex vivo expanded human autologous CD4+CD127lo/-CD25+ polyclonal regulatory T cells (Polyclonal Tregs) plus Interleukin-2 (IL-2) administered to patients with Type 1 Diabetes Mellitus (T1DM) will be safe and biologically active. A Phase I trial with this cellular therapy plus IL-2 will lead the way for Phase II trials that test for efficacy based on preservation of C-peptide, reduced exogenous insulin requirements and improved glycemic control.

This is a Phase I safety/dosing study of Polyclonal Tregs + IL-2 in patients with T1DM.

The Tregs will be expanded using an established protocol utilizing anti-CD3/anti-CD28 beads plus IL-2. The study will involve 2 dosing cohorts of 6-8 T1DM patients each. The primary objective of this study is to assess the safety of Tregs + IL-2 and survival of Tregs in patients with recent onset T1DM who receive infusions of autologous Tregs + IL-2. The study will also assess potential effects of Tregs on beta cell function and the autoimmune response.

Subjects will receive Polyclonal Tregs at doses of 3 or 20x10^6 cells/kg. The dose of Tregs is selected based on a combination of considerations of manufacturing capacity, a predicted efficacious dose, and the available safety data of the Treg product currently in clinical trials. The IL-2 dose will be 1 x10^6 IU subcutaneously, given daily for 5 consecutive days at the completion of the cell infusion and again after 1 month. This dose is based on recent studies from Klatzmann et al. in T1DM, where the dose was found to be effective in a selective Treg expansion, well tolerated, and without an acute decline in beta cell function (Rosenzwajg et al., 2015).

Being tested
PolyTregs+IL-2
Keywords
Diabetes, Treg, Proluekin
Medical subject headings
Diabetes Mellitus, Type 1, Diabetes Mellitus

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • PolyTregs+IL-2Biological

    PolyTregs will be infused into the patient in a single infusion. The first cohort will receive 3 x10^6 cells. The second cohort will receive 20x10^6 cells. Following the day 0 infusion of polyclonal Tregs, subjects will receive two 5-day courses of IL-2 (1 x 106 IU daily), the first on days 3-7 and the second on days 38-42. Administration of the second course of IL-2 may be delayed or withheld depending on threshold criteria for peripheral blood Treg frequencies and MMTT-stimulated C-peptide levels determined on day 28.

Study groups in NCT02772679
Study groupRoleWhat they receive
PolyTregs+IL-2ExperimentalPatients with type 1 diabetes mellitus will receive ex vivo expanded human autologous polyclonal regulatory T cells plus IL-2
Receives: Biological: PolyTregs+IL-2

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Adverse events

    Adverse events of special interest: including infections, malignancies, safety of Treg infusions, and local and systemic reactions to IL-2.

    Measured: up to 3 years

  2. Survival of Tregs

    Comparison of the survival of graded doses of Tregs and IL-2. Calculating the half-life of infused deuterium-labeled Tregs in peripheral circulation will be used to assess the survival of Tregs.

    Measured: up to 3 years

Secondary outcomes (9)

  1. C-peptide response

    Change in beta cell function over time, as assessed by change in C-peptide area under curve in response to serial mixed meal tolerance tests. Analysis will include a comparison to recent data available from TrialNet placebo treated subjects.

    Measured: up to 3 years

  2. Insulin use

    Insulin use in units per kilogram body weight per day

    Measured: up to 3 years

  3. HbA1c levels

    Measured: up to 3 years

  4. Severe hypoglycemic events

    Severe hypoglycemic events as defined by the inability to selftreat and/or the requirement for glucagon injection

    Measured: up to 3 years

  5. Proportion of subjects who achieve at least a 13-week reduction in insulin dose to < 0.5 units/kg in each treatment arm

    Measured: up to 3 years

  6. Analysis of the effects of IL-2 on Treg kinetics and phenotype

    Measured: up to 3 years

  7. Levels of unmethylated insulin DNA (assay of beta cell death)

    Measured: up to 3 years

  8. Analysis of autoantibodies, enumeration and phenotypes islet antigen tetramer+ CD8, intracellular cytokine staining of T cells, serum proteomics, cytokines, and Treg phenotyping and functional assays

    Measured: up to 3 years

  9. Analysis of general immune response as assessed by, for example, viral tetramer+ CD8 cells and effects of Treg infusions on peripheral blood cells measured by flow cytometry including T cell subsets, B cells and other innate cell subsets

    Measured: up to 3 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted13 May 2016 (estimated)
  2. Study startAug 2016
  3. Primary completion27 Aug 2021
  4. Study completion27 Aug 2021

Resources

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 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
16 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02772679
Sponsor's protocol ID
16-19632
Acronym
TILT
Status last verified
Oct 2021
First submitted
10 May 2016
Last updated
19 Oct 2021
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
Individual data sharing
No

Publications

  • Chatenoud L, Bluestone JA. CD3-specific antibodies: a portal to the treatment of autoimmunity. Nat Rev Immunol. 2007 Aug;7(8):622-32. doi: 10.1038/nri2134. Epub 2007 Jul 20.

    PubMed 17641665

  • Ahmadzadeh M, Rosenberg SA. IL-2 administration increases CD4+ CD25(hi) Foxp3+ regulatory T cells in cancer patients. Blood. 2006 Mar 15;107(6):2409-14. doi: 10.1182/blood-2005-06-2399. Epub 2005 Nov 22.

    PubMed 16304057

  • Ash S, Yarkoni S, Askenasy N. Lymphopenia is detrimental to therapeutic approaches to type 1 diabetes using regulatory T cells. Immunol Res. 2014 Jan;58(1):101-5. doi: 10.1007/s12026-013-8476-x.

    PubMed 24371009

  • Atkins MB. Interleukin-2: clinical applications. Semin Oncol. 2002 Jun;29(3 Suppl 7):12-7. doi: 10.1053/sonc.2002.33077.

    PubMed 12068383

  • Bailey-Bucktrout SL, Martinez-Llordella M, Zhou X, Anthony B, Rosenthal W, Luche H, Fehling HJ, Bluestone JA. Self-antigen-driven activation induces instability of regulatory T cells during an inflammatory autoimmune response. Immunity. 2013 Nov 14;39(5):949-62. doi: 10.1016/j.immuni.2013.10.016.

    PubMed 24238343

  • Bayer AL, Pugliese A, Malek TR. The IL-2/IL-2R system: from basic science to therapeutic applications to enhance immune regulation. Immunol Res. 2013 Dec;57(1-3):197-209. doi: 10.1007/s12026-013-8452-5.

    PubMed 24214027

  • Bluestone JA. Regulatory T-cell therapy: is it ready for the clinic? Nat Rev Immunol. 2005 Apr;5(4):343-9. doi: 10.1038/nri1574.

    PubMed 15775994

  • Buckner JH. Mechanisms of impaired regulation by CD4(+)CD25(+)FOXP3(+) regulatory T cells in human autoimmune diseases. Nat Rev Immunol. 2010 Dec;10(12):849-59. doi: 10.1038/nri2889.

    PubMed 21107346

  • Castela E, Le Duff F, Butori C, Ticchioni M, Hofman P, Bahadoran P, Lacour JP, Passeron T. Effects of low-dose recombinant interleukin 2 to promote T-regulatory cells in alopecia areata. JAMA Dermatol. 2014 Jul;150(7):748-51. doi: 10.1001/jamadermatol.2014.504.

    PubMed 24872229

  • Churlaud G, Jimenez V, Ruberte J, Amadoudji Zin M, Fourcade G, Gottrand G, Casana E, Lambrecht B, Bellier B, Piaggio E, Bosch F, Klatzmann D. Sustained stimulation and expansion of Tregs by IL2 control autoimmunity without impairing immune responses to infection, vaccination and cancer. Clin Immunol. 2014 Apr;151(2):114-26. doi: 10.1016/j.clim.2014.02.003. Epub 2014 Feb 19.

    PubMed 24576619

  • Couri CE, Oliveira MC, Stracieri AB, Moraes DA, Pieroni F, Barros GM, Madeira MI, Malmegrim KC, Foss-Freitas MC, Simoes BP, Martinez EZ, Foss MC, Burt RK, Voltarelli JC. C-peptide levels and insulin independence following autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA. 2009 Apr 15;301(15):1573-9. doi: 10.1001/jama.2009.470.

    PubMed 19366777

  • Diaz-de-Durana Y, Lau J, Knee D, Filippi C, Londei M, McNamara P, Nasoff M, DiDonato M, Glynne R, Herman AE. IL-2 immunotherapy reveals potential for innate beta cell regeneration in the non-obese diabetic mouse model of autoimmune diabetes. PLoS One. 2013 Oct 24;8(10):e78483. doi: 10.1371/journal.pone.0078483. eCollection 2013.

    PubMed 24205242

  • Dirice E, Kahraman S, Jiang W, El Ouaamari A, De Jesus DF, Teo AK, Hu J, Kawamori D, Gaglia JL, Mathis D, Kulkarni RN. Soluble factors secreted by T cells promote beta-cell proliferation. Diabetes. 2014 Jan;63(1):188-202. doi: 10.2337/db13-0204. Epub 2013 Oct 2.

    PubMed 24089508

  • Garg G, Tyler JR, Yang JH, Cutler AJ, Downes K, Pekalski M, Bell GL, Nutland S, Peakman M, Todd JA, Wicker LS, Tree TI. Type 1 diabetes-associated IL2RA variation lowers IL-2 signaling and contributes to diminished CD4+CD25+ regulatory T cell function. J Immunol. 2012 May 1;188(9):4644-53. doi: 10.4049/jimmunol.1100272. Epub 2012 Mar 28.

    PubMed 22461703

  • Grinberg-Bleyer Y, Baeyens A, You S, Elhage R, Fourcade G, Gregoire S, Cagnard N, Carpentier W, Tang Q, Bluestone J, Chatenoud L, Klatzmann D, Salomon BL, Piaggio E. IL-2 reverses established type 1 diabetes in NOD mice by a local effect on pancreatic regulatory T cells. J Exp Med. 2010 Aug 30;207(9):1871-8. doi: 10.1084/jem.20100209. Epub 2010 Aug 2.

    PubMed 20679400

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing PolyTregs+IL-2 in people with Type 1 Diabetes Mellitus, run by Jeffrey Bluestone at 2 sites in United States.

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 6 inclusion and 8 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: finished, as of the sponsor's last update on 19 Oct 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. 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 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

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 is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

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?

Adverse events (time frame: up to 3 years). The study lists 2 primary outcomes in all. 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 NCT02772679, which also lists 35 linked publications.

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 19 Oct 2021.

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