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Type 1 Diabetes MellitusPhase 1TregNCT01210664

T1DM Immunotherapy Using CD4+CD127lo/-CD25+ Polyclonal Tregs

A Phase 1 study testing Ex vivo Expanded Human Autologous Polyclonal Regulatory T Cells in people with Type 1 Diabetes Mellitus, run by University of California, San Francisco 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 investigational therapy under study in this trial, regulatory T cells (Tregs), offers the hope of stabilizing further destruction of insulin producing beta cells in type 1 diabetes. Tregs are a specialized subset of T cells that function to control the immune response. 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?
Ex vivo Expanded Human Autologous Polyclonal Regulatory T Cells
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
Nov 2010to Jan 2017
Phase
Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

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 screening according to the American Diabetes Association criteria
  • Between 18 and 45 years of age
  • Positive test for Epstein-Barr antibody
  • Positive test for at least one of the following antibodies:
  • ICA512-antibody
  • ICA
Show all 11Show fewer
  • GAD65-antibody
  • Insulin (if assessed within 10 days of the onset of insulin therapy)
  • ZnT8
  • Peak C-peptide >0.1 pmol/ml (>0.3 ng/ml) during MMTT challenge
  • Adequate venous access to support draw of 400 ml whole blood and infusion of investigational therapy

Who cannot join

  • Hemoglobin <10.0 g/dL; leukocytes <3,000/µL; neutrophils <1,500/µL; lymphocytes <800/µL; platelets <100,000/µL
  • Regulatory T cells present in peripheral blood at <10 per µl as determined by flow cytometry
  • Serologic evidence of HIV-1 or HIV-2 infection
  • Evidence of current hepatitis B as demonstrated by HBsAg or circulating hepatitis B genomes
  • Serologic evidence of hepatitis C infection
  • Detectable circulating EBV or CMV genomes or active infection
Show all 11Show fewer
  • Positive PPD skin test defined as greater than or equal to 10 mm induration
  • 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 7.5mg 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
  • Any chronic illness or prior treatment which in the opinion of the investigator should preclude participation in the trial
  • Pregnant or breastfeeding women, any female who is unwilling to use a reliable and effective form of contraception for 2 years afer Treg dosing and any male who is unwilling to use a reliable and effective form of contraception for 3 months after Treg dosing.

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 I Safety Trial of CD4+CD127lo/-CD25+ Polyclonal Treg Adoptive Immunotherapy for the Treatment of Type 1 Diabetes

The investigational therapy under study in this trial, regulatory T cells (Tregs), offers the hope of stabilizing further destruction of insulin producing beta cells in type 1 diabetes. Tregs are a specialized subset of T cells that function to control the immune response. Pre-clinical studies in non-obese diabetic mice have demonstrated that adoptive transfer of Tregs can slow diabetes progression and, in some cases, reverse new onset diabetes. The primary purpose of this Phase 1 study is to assess the safety and feasibility of intravenous infusion of ex vivo selected and expanded autologous polyclonal Tregs in patients with type 1 diabetes (T1DM) to support dose selection for a future efficacy trial. The study also aims to assess the effect of Tregs on beta cell function as well as on other measures of diabetes severity and the autoimmune response underlying T1DM.

Read the detailed description

Currently, there is no approved medical treatment for preservation of the body's ability to produce insulin in patients with Type 1 Diabetes Mellitus (T1DM), and the progression of the disease can have devastating consequences. Inadequate blood glucose control results in many long term complications including kidney disease, blindness, amputation and nerve damage. In spite of the advances in insulin therapy and subsequent glucose control, patients are required to infuse insulin subcutaneously daily throughout their lives, monitor their diet and blood sugar levels, and deal with life-long uncertainties. The investigational therapy under study in this trial, regulatory T cells (Tregs), offers the hope of stabilizing diabetes. Tregs are a specialized subset of T cells that function to control the immune response. Pre-clinical studies in non-obese diabetic mice have demonstrated that adoptive transfer of Tregs can slow diabetes progression and, in some cases, reverse new onset diabetes. The primary objective of this study is to assess the safety of a single intravenous infusion of Tregs in patients with T1DM. The study will also assess the effect of Tregs on insulin-producing beta cell function as well as other outcomes related to diabetes management. Researchers will isolate Tregs from the patient's own blood using specific T cell surface markers (CD4, CD25, and CD127). This subset of cells is then expanded in the laboratory by co-stimulating with anti-CD3 and anti-CD28 immobilized on magnetic beads, and with the use of growth medium containing human serum and IL-2. Following the 14-day expansion, anti-CD3/anti-CD28 beads will be removed and the Tregs will be concentrated and consolidated. The cells will then be resuspended in sterile infusion solution at the required concentration and infused back into the patient through a standard peripheral intravenous line. Subjects will be observed overnight in the clinical research center for any possible side effects following the infusion. A total of 14 subjects will be enrolled. The study will involve 4 dosing cohorts with 3 or 4 adults in each cohort. Each cohort will receive increasing amounts of Tregs. Subjects will be followed over five years to assess safety of the Treg therapy.

Being tested
Ex vivo Expanded Human Autologous Polyclonal Regulatory T Cells
Keywords
Diabetes, Treg
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.

  • Ex vivo Expanded Human Autologous Polyclonal Regulatory T CellsBiological

    Also called Tregs

    The researchers will multiply/expand the Tregs in the laboratory using anti-CD3/anti-CD28 coated beads plus IL-2. Then, the Tregs will be infused back into the patient in a single infusion. The first cohort will receive 0.05 x10^8 cells. The second cohort will receive 0.4 x10^8 cells. The third cohort will receive 3.2 x10^8 cells. The fourth cohort will receive 26 x10^8 cells.

Study groups in NCT01210664
Study groupRoleWhat they receive
Polyclonal Regulatory T CellsExperimentalPatients with Type 1 Diabetes Mellitus will have their regulatory T cells (Tregs) isolated by researchers and receive Ex vivo Expanded Human Autologous Polyclonal Regulatory T Cells by infusion
Receives: Biological: Ex vivo Expanded Human Autologous Polyclonal Regulatory T Cells

What is being measured

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

  1. Adverse Events (AEs) as a Measure of Safety and Tolerability

    The number of AEs are reported by cohort and severity.

    Measured: Mean follow-up of 31 months

  2. Number of Participants Experiencing Severe or Life Threatening Laboratory Abnormalities

    Laboratory measures tested include: hematology, blood chemistry, endocrine values, autoantibodies, and ophthalmologic exam results

    Total number of participants experiencing severe or life-threatening laboratory abnormalities is reported for each cohort. Events reported include hyperglycemia and hypoglycemia.

    Measured: Mean follow-up of 31 months

Secondary outcomes (3)

  1. Percent Change From Baseline in C-peptide Area Under the Curve

    Secondary diabetes-related outcome measure: C-peptide response during mixed meal tolerance test at 26 and 52 weeks, reported as the change from baseline in the area under the curve.

    Measured: 26 and 52 weeks from baseline

  2. Insulin Use

    Secondary diabetes-related outcome measure will include insulin use

    Measured: up to 104 weeks

  3. Hemoglobin A1c

    Secondary diabetes-related outcome measure will include hemoglobin A1c

    Measured: Up to 104 weeks

Timeline

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

  1. First posted28 Sep 2010 (estimated)
  2. Study startNov 2010
  3. Primary completionDec 2016
  4. Study completionJan 2017

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
NCT01210664
Sponsor's protocol ID
UCSFDC411AI
Other IDs
JDRF4-2005-1168
Acronym
Treg
Status last verified
Jun 2018
First submitted
23 Sep 2010
Last updated
11 Jul 2018
Data monitoring committee
Yes

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

  • Saudek F, Havrdova T, Boucek P, Karasova L, Novota P, Skibova J. Polyclonal anti-T-cell therapy for type 1 diabetes mellitus of recent onset. Rev Diabet Stud. 2004 Summer;1(2):80-8. doi: 10.1900/RDS.2004.1.80. Epub 2004 Aug 10.

    PubMed 17491669

  • 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

  • Tang Q, Bluestone JA. Regulatory T-cell physiology and application to treat autoimmunity. Immunol Rev. 2006 Aug;212:217-37. doi: 10.1111/j.0105-2896.2006.00421.x.

    PubMed 16903917

  • Tang Q, Henriksen KJ, Bi M, Finger EB, Szot G, Ye J, Masteller EL, McDevitt H, Bonyhadi M, Bluestone JA. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med. 2004 Jun 7;199(11):1455-65. doi: 10.1084/jem.20040139.

    PubMed 15184499

  • Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S, Gottlieb PA, Kapranov P, Gingeras TR, Fazekas de St Groth B, Clayberger C, Soper DM, Ziegler SF, Bluestone JA. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med. 2006 Jul 10;203(7):1701-11. doi: 10.1084/jem.20060772. Epub 2006 Jul 3.

    PubMed 16818678

  • Putnam AL, Brusko TM, Lee MR, Liu W, Szot GL, Ghosh T, Atkinson MA, Bluestone JA. Expansion of human regulatory T-cells from patients with type 1 diabetes. Diabetes. 2009 Mar;58(3):652-62. doi: 10.2337/db08-1168. Epub 2008 Dec 15.

    PubMed 19074986

  • Levine BL. T lymphocyte engineering ex vivo for cancer and infectious disease. Expert Opin Biol Ther. 2008 Apr;8(4):475-89. doi: 10.1517/14712598.8.4.475.

    PubMed 18352851

  • Rapoport AP, Stadtmauer EA, Aqui N, Vogl D, Chew A, Fang HB, Janofsky S, Yager K, Veloso E, Zheng Z, Milliron T, Westphal S, Cotte J, Huynh H, Cannon A, Yanovich S, Akpek G, Tan M, Virts K, Ruehle K, Harris C, Philip S, Vonderheide RH, Levine BL, June CH. Rapid immune recovery and graft-versus-host disease-like engraftment syndrome following adoptive transfer of Costimulated autologous T cells. Clin Cancer Res. 2009 Jul 1;15(13):4499-507. doi: 10.1158/1078-0432.CCR-09-0418. Epub 2009 Jun 9.

    PubMed 19509133

  • Levine BL, Bernstein WB, Aronson NE, Schlienger K, Cotte J, Perfetto S, Humphries MJ, Ratto-Kim S, Birx DL, Steffens C, Landay A, Carroll RG, June CH. Adoptive transfer of costimulated CD4+ T cells induces expansion of peripheral T cells and decreased CCR5 expression in HIV infection. Nat Med. 2002 Jan;8(1):47-53. doi: 10.1038/nm0102-47.

    PubMed 11786906

  • Miao D, Yu L, Eisenbarth GS. Role of autoantibodies in type 1 diabetes. Front Biosci. 2007 Jan 1;12:1889-98. doi: 10.2741/2195.

    PubMed 17127428

  • Wenzlau JM, Juhl K, Yu L, Moua O, Sarkar SA, Gottlieb P, Rewers M, Eisenbarth GS, Jensen J, Davidson HW, Hutton JC. The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17040-5. doi: 10.1073/pnas.0705894104. Epub 2007 Oct 17.

    PubMed 17942684

  • Bluestone JA, Buckner JH, Fitch M, Gitelman SE, Gupta S, Hellerstein MK, Herold KC, Lares A, Lee MR, Li K, Liu W, Long SA, Masiello LM, Nguyen V, Putnam AL, Rieck M, Sayre PH, Tang Q. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci Transl Med. 2015 Nov 25;7(315):315ra189. doi: 10.1126/scitranslmed.aad4134.

    PubMed 26606968

  • Dong S, Hiam-Galvez KJ, Mowery CT, Herold KC, Gitelman SE, Esensten JH, Liu W, Lares AP, Leinbach AS, Lee M, Nguyen V, Tamaki SJ, Tamaki W, Tamaki CM, Mehdizadeh M, Putnam AL, Spitzer MH, Ye CJ, Tang Q, Bluestone JA. The effect of low-dose IL-2 and Treg adoptive cell therapy in patients with type 1 diabetes. JCI Insight. 2021 Sep 22;6(18):e147474. doi: 10.1172/jci.insight.147474.

    PubMed 34324441

  • Gitelman SE, Bluestone JA. Regulatory T cell therapy for type 1 diabetes: May the force be with you. J Autoimmun. 2016 Jul;71:78-87. doi: 10.1016/j.jaut.2016.03.011. Epub 2016 Apr 28.

    PubMed 27133597

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Ex vivo Expanded Human Autologous Polyclonal Regulatory T Cells in people with Type 1 Diabetes Mellitus, run by University of California, San Francisco 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 11 inclusion and 11 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 11 Jul 2018. 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?

Yes. Results are posted in the registry (first posted 11 Jul 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

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 (AEs) as a Measure of Safety and Tolerability (time frame: Mean follow-up of 31 months). 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 NCT01210664, which also lists 15 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 11 Jul 2018.

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