T1DM Immunotherapy Using CD4+CD127lo/-CD25+ Polyclonal Tregs (Treg)

Tracking Information
First Submitted Date ICMJE	September 23, 2010
First Posted Date ICMJE	September 28, 2010
Last Update Posted Date	May 20, 2016
Study Start Date ICMJE	November 2010
Estimated Primary Completion Date	December 2016 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: September 27, 2010)	Number of Participants with Adverse events as a Measure of Safety and Tolerability. [ Time Frame: Up to 5 years ]; Primary outcome measures will be the number of participants with adverse events, laboratory abnormalities and other signs of toxicity. Particular focus will be on the number and severity of infusion reactions, complications related to infection, and any potential negative impact on the course of diabetes.
Original Primary Outcome Measures ICMJE	Same as current
Change History	Complete list of historical versions of study NCT01210664 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: September 27, 2010)	C-peptide response [ Time Frame: Up to 5 years ]Secondary diabetes-related outcome measure will include C-peptide response during mixed meal tolerance tests at 26 and 52 weeks; Insulin Use [ Time Frame: Up to 5 years ]Secondary diabetes-related outcome measure will include insulin use; Hemoglobin A1c [ Time Frame: Up to 5 years ]Secondary diabetes-related outcome measure will include hemoglobin A1c; Immunologic Markers [ Time Frame: Up to 5 years ]Secondary surrogate immunologic markers will include those related to general immune function and those related to the diabetes autoimmune response.
Original Secondary Outcome Measures ICMJE	Same as current
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	T1DM Immunotherapy Using CD4+CD127lo/-CD25+ Polyclonal Tregs
Official Title ICMJE	A Phase I Safety Trial of CD4+CD127lo/-CD25+ Polyclonal Treg Adoptive Immunotherapy for the Treatment of Type 1 Diabetes
Brief 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. 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.
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.
Study Type ICMJE	Interventional
Study Phase	Phase 1
Study Design ICMJE	Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	Type 1 Diabetes Mellitus
Intervention ICMJE	Biological: Ex vivo Expanded Human Autologous Polyclonal Regulatory T Cells; 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.; Other Name: Tregs
Study Arms	Experimental: Polyclonal Regulatory T Cells; Patients 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; Intervention: Biological: Ex vivo Expanded Human Autologous Polyclonal Regulatory T Cells
Publications *	Chatenoud L, Bluestone JA. CD3-specific antibodies: a portal to the treatment of autoimmunity. Nat Rev Immunol. 2007 Aug;7(8):622-32. Epub 2007 Jul 20. Review.; 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. Epub 2004 Aug 10.; Couri CE, Oliveira MC, Stracieri AB, Moraes DA, Pieroni F, Barros GM, Madeira MI, Malmegrim KC, Foss-Freitas MC, Simões 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.; Tang Q, Bluestone JA. Regulatory T-cell physiology and application to treat autoimmunity. Immunol Rev. 2006 Aug;212:217-37. Review.; 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.; 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. Epub 2006 Jul 3.; 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.; 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 . Review.; 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.; 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.; Miao D, Yu L, Eisenbarth GS. Role of autoantibodies in type 1 diabetes. Front Biosci. 2007 Jan 1;12:1889-98. Review.; 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. Epub 2007 Oct 17.; 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.; 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. Review.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Active, not recruiting
Estimated Enrollment ICMJE; (submitted: September 27, 2010)	14
Original Estimated Enrollment ICMJE	Same as current
Estimated Study Completion Date	March 2017
Estimated Primary Completion Date	December 2016 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	Inclusion Criteria: 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 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 Exclusion Criteria: 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; 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.
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years to 45 Years (Adult)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT01210664
Other Study ID Numbers ICMJE	UCSFDC411AI; JDRF4-2005-1168 ( Other Grant/Funding Number: JDRF )
Has Data Monitoring Committee	Yes
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	University of California, San Francisco
Study Sponsor ICMJE	University of California, San Francisco
Collaborators ICMJE	Juvenile Diabetes Research Foundation; National Institute of Allergy and Infectious Diseases (NIAID)
Investigators ICMJE	Study Chair: Stephen E Gitelman, MD University of California, San Francisco Study Director: Jeffrey Bluestone, PhD University of California, San Francisco Principal Investigator: Kevan Herold, MD Yale University
PRS Account	University of California, San Francisco
Verification Date	May 2016
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP