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Trial record 2 of 27 for:    Tregs | Diabetes

T1DM Immunotherapy Using Polyclonal Tregs + IL-2 (TILT)

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2016 by University of California, San Francisco
Yale University
Information provided by (Responsible Party):
Jeffrey Bluestone, University of California, San Francisco Identifier:
First received: May 10, 2016
Last updated: August 10, 2016
Last verified: August 2016
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.

Condition Intervention Phase
Type 1 Diabetes Mellitus
Biological: Treg+IL-2
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1 Trial of CD4+CD127lo/-CD25+ Polyclonal Treg Adoptive Immunotherapy With Interleukin-2 for the Treatment of Type 1 Diabetes

Resource links provided by NLM:

Further study details as provided by University of California, San Francisco:

Primary Outcome Measures:
  • Adverse events [ Time Frame: up to 3 years ] [ Designated as safety issue: Yes ]
    Adverse events of special interest: including infections, malignancies, safety of Treg infusions, and local and systemic reactions to IL-2.

  • Survival of Tregs [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]
    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.

Secondary Outcome Measures:
  • C-peptide response [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]
    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.

  • Insulin use [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]
    Insulin use in units per kilogram body weight per day

  • HbA1c levels [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]
  • Severe hypoglycemic events [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]
    Severe hypoglycemic events as defined by the inability to selftreat and/or the requirement for glucagon injection

  • Proportion of subjects who achieve at least a 13-week reduction in insulin dose to < 0.5 units/kg in each treatment arm [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]
  • Analysis of the effects of IL-2 on Treg kinetics and phenotype [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]
  • Levels of unmethylated insulin DNA (assay of beta cell death) [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]
  • 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 [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]
  • 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 [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 16
Study Start Date: August 2016
Estimated Study Completion Date: December 2021
Estimated Primary Completion Date: July 2021 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treg+IL-2
Patients with type 1 diabetes mellitus will receive ex vivo expanded human autologous polyclonal regulatory T cells plus IL-2
Biological: Treg+IL-2
Tregs 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.

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 3 dosing cohorts of 4 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 50x106, 350x106 or 1x109 cells. 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 1x106 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 selective Treg expansion, well tolerated, and without acute decline in beta cell function (Rosenzwajg et al., 2015).


Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Diagnosis of T1DM within >3 and <24 months of day 0 according to the American Diabetes Association standard criteria.
  2. 18 to 45 years of age on day of screening visit.
  3. 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).
  4. Peak stimulated C-peptide level >0.2 pmol/mL (0.6 ng/ml) following an MMTT.
  5. Weight of > 40 kg
  6. 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

Exclusion Criteria:

  1. Hemoglobin <10.0 g/dL; leukocytes <3,000/μL; neutrophils <1,500/μL; lymphocytes <800μL; platelets <100,000/μL
  2. Any sign of significant chronic active infection (e.g., hepatitis, tuberculosis, EBV, CMV, or toxoplasmosis), or screening laboratory evidence consistent with a significant chronic active infection (such as positive for HIV, PPD, or HBsAg).
  3. 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.
  4. 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.
  5. History of malignancy (including squamous cell carcinoma of the skin or cervix) except adequately treated basal cell carcinoma
  6. 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
  7. Any condition that, in the investigator's opinion, may compromise study participation or may confound the interpretation of the study results.
  8. 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT02772679

Contact: Jingying Xu, Ph.D.

United States, California
University of California, San Francisco Medical Center Recruiting
San Francisco, California, United States, 94143
Contact    844-814-8273   
Principal Investigator: Stephen E Gitelman, MD         
United States, Connecticut
Yale University Not yet recruiting
New Haven, Connecticut, United States, 06519
Contact: Linda Rink, RN    203-444-7334   
Principal Investigator: Kevan Herold, MD         
Sponsors and Collaborators
Jeffrey Bluestone
Yale University
  More Information


Responsible Party: Jeffrey Bluestone, Professor, University of California, San Francisco Identifier: NCT02772679     History of Changes
Other Study ID Numbers: 16-19632 
Study First Received: May 10, 2016
Last Updated: August 10, 2016
Health Authority: United States: Food and Drug Administration
Individual Participant Data  
Plan to Share IPD: No

Keywords provided by University of California, San Francisco:

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 1
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases processed this record on September 27, 2016