Back to resultsT1DM Immunotherapy Using Polyclonal Tregs + IL-2 (TILT)
Primary Purpose
Type 1 Diabetes Mellitus
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
PolyTregs+IL-2
Sponsored by
About this trial
This is an interventional treatment trial for Type 1 Diabetes Mellitus focused on measuring Diabetes, Treg, Proluekin
Eligibility Criteria
Inclusion Criteria:
- 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
Exclusion Criteria:
- 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.
Sites / Locations
- University of California, San Francisco Medical Center
- Yale University
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
PolyTregs+IL-2
Arm Description
Patients with type 1 diabetes mellitus will receive ex vivo expanded human autologous polyclonal regulatory T cells plus IL-2
Outcomes
Primary Outcome Measures
Adverse events
Adverse events of special interest: including infections, malignancies, safety of Treg infusions, and local and systemic reactions to IL-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.
Secondary Outcome Measures
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.
Insulin use
Insulin use in units per kilogram body weight per day
HbA1c levels
Severe hypoglycemic events
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
Analysis of the effects of IL-2 on Treg kinetics and phenotype
Levels of unmethylated insulin DNA (assay of beta cell death)
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
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
Full Information
NCT ID
NCT02772679
First Posted
May 10, 2016
Last Updated
October 15, 2021
Sponsor
Jeffrey Bluestone
Collaborators
Yale University
1. Study Identification
Unique Protocol Identification Number
NCT02772679
Brief Title
T1DM Immunotherapy Using Polyclonal Tregs + IL-2
Acronym
TILT
Official Title
A Phase 1 Trial of CD4+CD127lo/-CD25+ Polyclonal Treg Adoptive Immunotherapy With Interleukin-2 for the Treatment of Type 1 Diabetes
Study Type
Interventional
2. Study Status
Record Verification Date
October 2021
Overall Recruitment Status
Completed
Study Start Date
August 2016 (undefined)
Primary Completion Date
August 27, 2021 (Actual)
Study Completion Date
August 27, 2021 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Jeffrey Bluestone
Collaborators
Yale University
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Data Monitoring Committee
Yes
5. Study Description
Brief 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.
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).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Type 1 Diabetes Mellitus
Keywords
Diabetes, Treg, Proluekin
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
16 (Actual)
8. Arms, Groups, and Interventions
Arm Title
PolyTregs+IL-2
Arm Type
Experimental
Arm Description
Patients with type 1 diabetes mellitus will receive ex vivo expanded human autologous polyclonal regulatory T cells plus IL-2
Intervention Type
Biological
Intervention Name(s)
PolyTregs+IL-2
Intervention Description
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.
Primary Outcome Measure Information:
Title
Adverse events
Description
Adverse events of special interest: including infections, malignancies, safety of Treg infusions, and local and systemic reactions to IL-2.
Time Frame
up to 3 years
Title
Survival of Tregs
Description
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.
Time Frame
up to 3 years
Secondary Outcome Measure Information:
Title
C-peptide response
Description
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.
Time Frame
up to 3 years
Title
Insulin use
Description
Insulin use in units per kilogram body weight per day
Time Frame
up to 3 years
Title
HbA1c levels
Time Frame
up to 3 years
Title
Severe hypoglycemic events
Description
Severe hypoglycemic events as defined by the inability to selftreat and/or the requirement for glucagon injection
Time Frame
up to 3 years
Title
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
Title
Analysis of the effects of IL-2 on Treg kinetics and phenotype
Time Frame
up to 3 years
Title
Levels of unmethylated insulin DNA (assay of beta cell death)
Time Frame
up to 3 years
Title
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
Title
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
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
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
Exclusion Criteria:
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.
Facility Information:
Facility Name
University of California, San Francisco Medical Center
City
San Francisco
State/Province
California
ZIP/Postal Code
94143
Country
United States
Facility Name
Yale University
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06519
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
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T1DM Immunotherapy Using Polyclonal Tregs + IL-2
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